Introduction
1. Amazingly, it was less than a year after the 1895 discovery of mysterious, or “X,” rays by German physicist Wilhem Röntgen that high-energy electromagnetic radiation machines became a medical technology. Homeopathic physician Dr. Emil Grubbe had one at the Hahnemann Medical College of Chicago, to treat carcinoma, but those early machines may have done more harm than good; Dr. Grubbe himself endured more than ninety operations for multiple cancers. Grubbe was an early adopter. It was Marie Curie’s discovery of radioactive elements that greatly broadened the use of radiation as a cancer therapy. Both Röntgen and Curie received Nobel Prizes for their work. Titus C. Evans, “Review of X-Ray Treatment—Its Origin, Birth, and Early History by Emil H. Grubbe,” Quarterly Review of Biology, 1951, 26:223.
2. These numbers are meant as a very broad illustration of concept and should in no way be confused with any statistical probability or scientific certainty that a rogue cell is not recognized by the immune system or will grow out to become something we would recognize as clinical cancer. The larger point is that the immune system is generally extremely successful at recognizing non-self and that random, infinite rolls of the dice render even the most exceptionally improbable outcomes inevitable. Factors like viral infection or certain chromosomal defects make those improbable outcomes less so.
3. Called pembrolizumab, it is a humanized monoclonal antibody that binds to and blocks the T cell’s PD-1 receptor. It is manufactured and sold by Merck under the brand name Keytruda.
4. Mr. Carter had metastatic melanoma, which had spread to his liver and brain, for which he underwent surgery and received radiation therapy, in addition to his immunotherapy.
5. The first to suggest this analogy to me was Dr. Daniel Chen.
One: Patient 101006 JDS
1. He made enough to get his own season tickets—Yankees, twenty-two years—not that he used all the tickets after he and his wife, an executive at the time with Interscope Records, moved to California.
2. He would have been cool with accounting regardless, but no doubt, representing rock-and-roll acts was the coolest version of accounting.
3. “Yesterday” is the most covered song of all time, according to the Guinness Book of World Records. It’s not difficult to believe it’s made royalties comparable to those of “Yellow Ribbon.”
4. Jeff’s diagnosis occurred in 2011. While it’s possible that he would have responded to the T cell side of this ligand interaction, the future of PD-1 was in that moment in a sort of limbo in terms of patient availability, as we’ll see in later chapters, and would not be approved by the FDA until 2014, years after Jeff Schwartz began PD-L1 trials and significantly later than he was expected to survive. Further, that initial PD-1 approval was only for metastatic melanoma. Approvals for other indications have followed and are continuing.
5. Sutent, which targets a tumor’s ability to eat and grow, is not, technically, “chemotherapy.” Though Schwartz was not privy to the identity of the drug he’d be testing, it was for the anti-PD-L1 checkpoint inhibitor atezolizumab, which would be marketed under the trade name Tecentriq. See Appendix A.
6. Avastin (bevacizumab) has since been approved as part of a combination therapy for several different cancer types, including metastatic renal cancer, when used with interferon alpha.
7. Brian Irving, Yan Wu, Ira Mellman, and Julia Kim.
8. The Chens have three children: a daughter, Isabelle; and two sons, Cameron and Noah.
Two: A Simple Idea
1. A privately printed monograph, “Creating Two Preeminent Institutions: The Legacy of Bessie Dashiell,” details aspects of the relationship between Dashiell and John D. Rockefeller Jr., and links it to Rockefeller’s subsequent foundational support of cancer research institutions Rockefeller University and Memorial Sloan Kettering Cancer Center. The slim volume was printed in very limited quantities in 1978 by the Vermont-based Woodstock Foundation (also Rockefeller supported), with a copy held in the collection of the Cancer Research Institute along with the Coley archive. Matt Tontonoz, CRI’s excellent science writer (now with Memorial Sloan Kettering Cancer Center), generously guided me to this and other sources used throughout the chapter.
Additional information comes from the indispensable resource of William B. Coley’s personal papers, collected by and significantly added to by his daughter, Helen Coley Nauts. Originally kept at CRI, they were donated upon. Nauts’s death in 2001 to the Yale University Library (Helen Coley Nauts papers MS 1785), where they are now being catalogued. That collection consists of patient files, correspondence, writings, subject files, and other materials documenting the careers of Helen and her father, as well as extensive material regarding his toxins. This collection fills 119 boxes, 117.5 linear feet of material.
2. This Pullman detail, found in several journal articles (e.g., David B. Levine, “Gibney as Surgeon-in-Chief: The Earlier Years, 1887–1900,” HSS Journal: The Musculoskeletal Journal of Hospital for Special Surgery, 2006, 2:95–101), surely sources from a personal interview with Coley’s daughter, Helen Coley Nauts, by the author Stephen S. Hall, whose 1997 volume on the history of immunology (A Commotion in the Blood: Life, Death, and the Immune System [New York: Henry Holt]) deserves particular acknowledgment as an invaluable resource and a much-recommended read. Mr. Hall was also generous enough to (briefly) switch roles and submit to an interview, for which this author is grateful.
3. New York Hospital was the country’s third oldest, established by a 1771 royal charter by England’s King George III, for the “reception of such patients as require medical treatment, chirurgical management and maniacs.” By the time Coley interned there it had outgrown its original building on Broadway between what is now Worth and Duane streets and had moved to a new building between Fifth and Sixth Avenues and West Fifteenth and Sixteenth Streets.
Plenty of fascinating detail can be found in an account of a physician’s address before the New York Hospital alumni board: “Old New York Hospital; Its Interesting History Retraced by Dr. D. B. St. John Roosa. Episode of the Doctors Mob. The Aftermath of a Fourth of July Celebration. Forty Years Ago—Surgery Then and Now,” New York Times, February 11, 1900.
4. Coley’s medical education had been a late decision, made only after he decided against studying law and had spent two years as a schoolmaster teaching the classics in Oregon. He’d gotten into Harvard Medical School’s three-year program as a second-year, owing to the experience of making horseback house calls with his physician uncle in rural southern Connecticut. He had been lucky enough, in his first year of residency, to be given a summer position replacing an absentee doctor at New York Hospital. The direct observation of human illness put the five-foot-eight young man a head above his peers in applying for positions, and when he landed back at New York Hospital as an intern, he found himself mentored by two of the most famous and influential surgeons in the country, Robert F. Weir and William T. Bull. His later appointments would include the Hospital for the Ruptured and Crippled, now the Hospital for Special Surgery.
5. As a result of the improvements of Lister and others, a surgeon’s art could be practiced with lessened probability of infection, which had plagued such procedures for thousands of years.
6. The date of the examination was October 1, 1890.
7. Rudolf Virchow especially had advanced the pathology of cancer as examined under the microscope, allowing it to be more systematically diagnosed.
8. Details of Dashiell’s case can be found in William B. Coley, “Contribution to the Knowledge of Sarcoma,” Annals of Surgery, 1891, 14:199–220.
9. W. B. Coley, “The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas: With a Report of Ten Original Cases,” American Journal of the Medical Sciences, 1893, 105:487–511.
10. From Coley’s collected writings we learn that Stein’s sarcoma had first presented itself in 1880 as a small spot on his cheek, which by the following year had grown to a mass that required surgery. It came quickly back and was again removed surgically the following year. When Stein arrived at New York Hospital two years later, the mass had returned, and it reportedly looked something like a small bunch of grapes. This was the mass Dr. Bull operated on, and again in 1884—eventually creating the abscessed wound, which would not close with skin grafts and which finally became infected. Coley, “The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas”; William B. Coley, “A Preliminary Note on the Treatment of Inoperable Sarcoma by the Toxic Products of Erysipelas,” Post-Graduate, 1893, 8:278–286; W. B. Coley, “The Treatment of Inoperable Sarcoma by Bacterial Toxins (The Mixed Toxins of the Streptococcus of Erysipelas and the Bacillus Prodigiosus),” Practitioner, 1909, 83:589–613; the archives of Cancer Research Institute; and other sources.
11. The German surgeon Friedrich Fehleisen established the association between the bacterium and the infection, as well as the first description of its appearance through a microscope. Friedrich Fehleisen, Die Aetiologie des Erysipels (Berlin: Theodor Fischer, 1883).
12. Until the discovery of antibiotics several decades later, there was no treatment for this infection.
13. Not just erysipelas but several other diseases, including ergotism and herpes zoster (shingles), had been referred to as St. Anthony’s Fire, after the Christian saint to whom those afflicted would appeal for healing. Around 1100, the Roman Catholic Order of St. Anthony was formed in France to care for those with the ailment.
14. Also that year, two different scientists, one Swedish, and one a US geologist, had independently suggested that increased human production of CO2 might result in global warming.
15. Emphasis mine. This 1909 reference and several others come from Coley’s papers at the Yale University Library (Helen Coley Nauts papers MS 1785). This reference was also recounted in Stephen Hall’s A Commotion in the Blood.
16. Anton Pavlovich Chekhov, Letters of Anton Chekhov to His Family and Friends, with Biographical Sketch, trans. Constance Garnett (New York: Macmillan, 1920).
17. Especially following fevers, infections, or both. A. Deidier, Dissertation Médicinal et Chirurgical sur les Tumeurs (Paris, 1725); U. Hobohm, “Fever and Cancer in Perspective,” Cancer Immunology, Immunotherapy, 2001, 50:391–396; W. Busch, “Aus der Sitzung der Medicinischen Section vom 13 November 1867,” Berliner Klinische Wochenschrift, 1868, 5:137; P. Bruns, “Die Heilwirkung des Erysipelas auf Geschwülste,” Beiträge zur Klinische Chirurgie, 1888, 3:443–446.
18. Arthur M. Silverstein, A History of Immunology, 2nd ed. (Boston: Academic Press / Elsevier, 2009).
19. William Boyd, “The Meaning of Spontaneous Regression,” Journal of the Canadian Association of Radiologists, 1957, 8:63; H. C. Nauts, “The Beneficial Effects of Bacterial Infections in Host Resistance to Cancer: End Results in 449 Cases,” Monograph 8 (New York: Cancer Research Institute, 1990).
20. Ilana Löwy, “Experimental Systems and Clinical Practices: Tumor Immunology and Cancer Immunotherapy, 1895–1980,” Journal of the History of Biology, 1994, 27:403–435.
In a similar experiment undertaken in 1868, a German scientist named W. Busch had intentionally infected a sarcoma patient with the erysipelas bacterium, Streptococcus pyogenes. After surgery, he had the patient recover in a hospital bed notorious for infecting every patient to inhabit it. This case was no exception, except that, as Busch reported, the resulting infection shrank the patient’s tumors. Whether it was also responsible for her death nine days later was not specified, but that death did not take away from his larger point: induced infection seemed to have an effect on cancer when nothing else did. If they could control the infection, perhaps they might create a cure.
21. Coley, “The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas”; W. B. Coley, “The Treatment of Inoperable Sarcoma by Bacterial Toxins,” Proceedings of the Royal Society of Medicine, 1910, 3(Surg Sect):1–48.
22. Zola case notes from Coley’s collected papers, Cancer Research Institute archives.
23. Zola lived on Manhattan’s Lower East Side, and his own niece risked her life to serve as his nurse. For her pains, she’d contract an erysipelas infection as well.
24. William B. Coley, “Further Observations upon the Treatment of Malignant Tumors with the Toxins of Erysipelas and Bacillus Prodigiosus, with a Report of 160 Cases,” Johns Hopkins Hospital Bulletin, 1896, 7:157–162.
25. S. A. Hoption Cann, J. P. van Netten, and C. van Netten, “Dr. William Coley and Tumour Regression: A Place in History or in the Future,” Postgraduate Medical Journal, 2003, 79:672–680; Coley, “The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas.”
Possibly Coley’s tepid language serves to cover for multiple scientific sins, including a failure to reproduce the remission experienced by Fred Stein, one Coley had only seen as briefly described anecdotally in Stein’s handwritten medical report. Coley believed that the problem was in his patient selection for the experiments—their sarcomas were too far advanced; otherwise, he wrote, “It would not have been too much to have looked for a permanent cure.” But here, Coley’s vague and subjective language suggests that he wasn’t seeing the results expected.
For all his insight, Coley was guilty of medicine’s original and cardinal sin of putting ego before evidence. But he was onto something and he knew it, and he would soon prove willing to tie himself to the mast once that course was set.
Perhaps this is the countervailing genius of ego: persistence in the face of what’s taken to be common sense. This was something I heard time and again while interviewing researchers. In science as everywhere, overconfidence in one’s own ideas is hubris, but confidence, or at least a conviction in logic and empiricism even when the data point to unpopular or impolitic conclusions is essential to the seeker of truth. The real breakthroughs come from those who are tenacious, undeterred, and undiscouraged early in an experiment. They have courage and conviction. But in the end, they must also do good science, make nonsubjective observations, and present good data. Coley didn’t do that. But his original observation had been astute, accurate, and important. He’d seen a spontaneous cancer remission and recognized it as science rather than miracle. And he doggedly pursued the experiments that might make use of that science.
26. This was the age of the bacteriologist, and even those who would not have regarded themselves thusly dabbled across the invisible and wholy arbitrary line separating the study of microscopy from that of the animals visible only through the microscope’s lens. The interest in “disease” vs. the interest in bacteria recognized the relevance of toxins to both patient and pathogen. The chemistry of those toxins, and the responses of factors in the blood against those toxins follow from this study. Some of the more well-known names of this group include Louis Pasteur, Emil von Behring, Élie Metchnikoff, Paul Ehrlich, and Robert Koch. Their variously conflicting and complimentary approaches toward bacteria as the agents of disease gave birth to what would become the field of immunology, and what was then called seritology—the study of the fluid portion of blood, after the red and white blood cells had been strained out through the microscopic pores of a porcelain filter. Immune response was still a black box mystery, but it was known that bacteria were responsible for some diseases, and vaccination against those bacteria was possible. And all of that was presumed to happen in this colorless fluid in the blood.
27. B. Wiemann and C. O. Starnes, “Coley’s Toxins, Tumor Necrosis Factor and Cancer Research: A Historical Perspective,” Pharmacology and Therapeutics, 1994, 64:529–564.
28. Hall, Commotion, p. 57.
29. New York Cancer Hospital had been founded by the city’s wealthy following news of the serial-cigar-smoking president Ulysses S. Grant’s diagnosis of throat cancer. It was the first cancer-specific hospital in the United States, the second in the world. Its original mission was primarily to care for the dying in comfort and relative luxury. The wards were designed to accommodate the most modern, medically hygienic requirements for airflow and personal patient ventilation, garnering praise from a New York Times reviewer, but ultimately had a little too much style to be practical; the round rooms, designed in order to keep filth and germs from accumulating in the corners, did not give themselves to practical partition, and the gothic French chateau–styled turrets soon became as decrepit as the royal manors of old Europe they were designed to invoke. They were eventually abandoned for more practical quarters and slated for demolition but are now preserved as landmark multi-million-dollar condominiums with fabulous Central Park views. Christopher Gray, “Streetscapes/Central Park West Between 105th and 106th Streets; In the 1880’s, the Nation’s First Cancer Hospital,” New York Times, December 28, 2003; New York City Landmarks Preservation Commission, Andrew S. Dolkart, and Matthew A. Postal, Guide to New York City Landmarks, 4th ed., ed. Matthew A. Postal (New York: John Wiley & Sons, 2009).
30. On April 21, 1892, Coley began injections on a forty-year-old man with an inoperable tumor in his back. It had been diagnosed as sarcoma and spread to his groin. After four weeks of steady injections a high fever was realized, and the patient began to respond in a manner similar to Zola’s. Coley described this reaction with the enthusiasm of a nature writer witnessing his first sunset at Grand Canyon: “From the beginning of the attack the change that took place in the tumor was nothing short of marvelous. It lost its luster and color and had shrunk visibly in size within twenty-four hours. Several sinuses formed the second day and discharged necrosed tumor tissues. A few days later the tumor of the groin, which was about the size of a goose egg and very hard when the inoculations were begun, broke down and discharged a large amount of tumor tissue. Three weeks from the date of the attack of erysipelas both tumors had entirely disappeared.” But Coley’s excitement would not last. The man’s tumors continued to grow back, and he continued to receive injections and surgeries before finally succumbing to a cancer in his abdomen three and a half years after his treatment had begun.
31. The subject of fever deserves its own chapter. The widespread use of antibiotics has saved countless lives from the ravages of infection, and they are routinely employed in postsurgical settings, where symptoms of infection, such as fever, are routinely suppressed. It may be worth considering whether this aspect of immune response is more than a symptom and side effect, and consider it a therapeutic aspect, with overlooked benefit. Fever has been shown to correspond to increased biochemical reaction rates and leukocyte proliferation, maturation, and activation. Fever also has been reported to have a palliative effect on pain. This paragraph is not a substitute for a more substantive examination of the topic, but a bookmark for further examination as to whether such a metabolically expensive physiological reaction triggered by the immune system would be conserved across species unless it had some benefit to survival.
32. Friedrich Fehleisen, the preeminent German physician using those same erysipelas injections at the Wurzburg clinic, had given up on the bacteria and been forced to resign his prestigious post due to patient deaths; this information appears in A Commotion in the Blood and was relayed to Stephen Hall by Otto Westphal.
33. Coley, “The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas.”
34. The biological term is attenuated.
35. Experiments by physician H. Roger of the Pasteur Institute, reported in a mellifluous French that renders bacteria elegant. H. Roger, “Contribution à l’étude expérimentale du streptocoque de l’érysipèle,” Revue de Médecine, 1892, 12:929–956.
36. S. pyogenes and Serratia marcescens. William B. Coley, “Treatment of Inoperable Malignant Tumors with the Toxines of Erysipelas and the Bacillus Prodigiosus,” Transactions of the American Surgical Association, 1894, 12:183–212.
37. Though Coley didn’t have the means to understand the immunologic and biochemical mechanisms of action of his toxin’s reported therapeutic effects, more recent experiments have demonstrated that the erysipelas bacterium had nothing to do with it. However, in the 1970s, experiments by legendary cancer immunotherapist Lloyd Old at MSKCC and others showed that the other bacteria Coley had utilized, B. prodigiosus, did create endotoxins that stimulated the immune system’s macrophages into producing powerful immune system messengers, cytokines including interferon (IF), interleukin (IL), and tumor necrosis factor (TNF). Boyce Rensberger, “Century-Old Cancer Treatment Reexamined,” Washington Post, September 18, 1985.
How these would have interacted with the tumor is another mystery, addressed in B. Wiemann and C. O. Starnes, “Coley’s Toxins, Tumor Necrosis Factor and Cancer Research: A Historical Perspective,” Pharmacology and Therapeutics, 1994, 64:529–564. Old and others (as we will see in later chapters) would continue to probe the mysteries of these molecules, and test them against a host of diseases, including cancer. Some were demonstrated to be powerful tools against tumors in animal models, and they were quickly, if prematurely, hailed on the covers of Newsweek and Time as the possible magic bullet cures for cancer; in humans they would be found to have powerful but uneven results—potent, sometimes curative, sometimes toxic, and generally poorly understood.
Those cytokines are covered in more detail in later chapters; some are now being reexamined in the light of the newest cancer breakthroughs, as important pieces of combination therapies.
38. William B. Coley, “The Treatment of Inoperable Malignant Tumors with the Toxins of Erysipelas and Bacillus Prodigosus,” Medical Record, 1895, 47:65–70.
39. Coley’s work met a great deal of resistance, and many of the leaders in the sarcoma and general medical world actively worked to discredit his work, going so far as to suggest that his remissions were invalid because his diagnoses had been wrong, and his patients never had cancer to begin with. As usual, the takedowns were heard more clearly than the retractions. In 1934, the editorial board of the Journal of the American Medical Association, which had declared Coley’s lifework invalid, changed its mind:
It appears, that undoubtedly the combined toxins of erysipelas and prodigiosus may sometimes play a significant role in preventing or retarding malignant recurrence or metastases; occasionally they may be curative in hopelessly inoperable neoplasms;… The Council has, for these reasons, retained Erysipelas and Prodigiosus Toxins-Coley in New and Nonofficial Remedies, with a view to facilitating further studies with the product.
Excerpted from “Council on Pharmacy and Chemistry: Erysipelas and Prodigiosus Toxins (Coley),” editorial, Journal of the American Medical Association, 1934, 103:1067–1069.
40. B. J. Johnston and E. T. Novales, “Clinical Effect of Coley’s Toxin. II. A Seven-Year Study,” Cancer Chemotherapy Reports, 1962, 21:43–68.
41. In 1992, the British journal Nature published a study by Charlie Starnes, a molecular immunologist who took a fresh look at William Coley’s data on inoperable sarcoma cancers that had received no treatment aside from Coley’s Toxins. What he found was, essentially, patient response rates far better than what anyone else had achieved to date in trying to treat these cancers by other means.
Some 10 percent of Coley’s patients saw remissions of at least twenty years, many longer. Set against the baseline of otherwise hopeless cases and 100 percent remission, use of the toxins showed promise worthy of investigation.
By the standards of most modern cancer studies, in which remission refers to a patient showing no evidence of disease (NED) for at least five years following therapy, the results were even more striking; seventy-three of Coley’s 154 sarcoma and lymphosarcoma patients—47 percent—were NED five years after treatment (Charlie O. Starnes, “Coley’s Toxins in Perspective,” Nature, 1992, 357:11–12).
It had taken nearly one hundred years before basic scientific research would catch up to what pioneering immunologist Lloyd Old called “the Coley Phenomenon”—the Tantalus-like purgatory of having perceived a mechanism in nature that might save millions of lives while lacking the tools to prove or use it.
“The cellular and molecular language of inflammation and immunity had to be understood,” Old said, “before the forces that Coley unleashed could be predictably translated into tumor cell destruction.”
42. Stephen Hall, in A Commotion in the Blood, quotes comments made by Nicholas Senn of Rush Medical College to his colleagues at the American Medical Association’s 1895 annual meeting: “The treatment of inoperable sarcoma and carcinoma with the mixed toxins, as advised and practiced by Coley, has been given a fair trial in the surgical clinic of Rush Medical College, and so far it has resulted uniformly in failure… Although I shall continue to resort to it in otherwise hopeless cases in the future, I have become satisfied that it will be abandoned in the near future and assigned to a place in the long list of obsolete remedies employed at different times in the treatment of malignant tumors beyond the reach of a radical operation.”
Hall also quotes comments Coley made to the Surgical Section of the Royal Society of Medicine in London in 1909, as rebuttal to two decades of criticism of his medicine and his character: “No one could see the results I saw and lose faith in the method. To see poor hopeless sufferers in the last stages of inoperable sarcoma show signs of improvement, to watch their tumors steadily disappear, and finally see them restored to life and health, was sufficient to keep up my enthusiasm. That only a few instead of the majority showed such brilliant results did not cause me to abandon the method, but only stimulated me to more earnest search for further improvements in the method.”
43. Hoption Cann et al., “Dr William Coley and Tumour Regression.”
44. In theory, the toxins could have been revived as a therapy, but because they were now listed as a “new” therapy, they’d be forced to go through a lengthy and expensive process of clinical trials for the FDA, hoping for an approval that might never come, for a formulation that would not be proprietary.
45. Hall, Commotion, p. 116.
46. As noted in the monograph “Creating Two Preeminent Institutions: The Legacy of Bessie Dashiell,” this was aided, once again, with Rockefeller money. There was philanthropic conflict between Coley’s appeals for funding for Memorial and John D. Rockefeller’s existing support of the laboratories at the eponymous and physically proximate Rockefeller Institute, which had been built in 1901 after young John Jr. urged his father to create something like the impressive European laboratories of Pasteur and Koch. Rockefeller’s scientific advisors didn’t see much progress coming from Coley’s work with “human material.” His secretary of the Rockefeller Institute, Jerome D. Green, agreed that their support for Memorial should be discontinued: Instead of funding Memorial directly, John Jr. started cutting checks directly to Coley.
47. From the letters of Helen Coley Nauts, Coley archive of the Cancer Research Institute, as researched by CRI staff science writer Matt Tontonoz.
48. So what might have happened differently? What if Memorial Sloan Kettering, under the guidance of Cornelius Rhoads, had not dismissed Coley’s appeals and his daughter’s letters, and put the resources of “the largest cancer hospital in the world” into a clinical evaluation of Coley’s bacterial toxin approach to immunotherapy? It’s impossible to say. Medicine in 1950 wouldn’t have had much more of an idea of what to make of Coley’s “miracle” cases than Coley himself had in 1890. The immune system was still a mystery. Cancer was still an enemy to be attacked and killed, by weapons developed with a wartime mentality. Immune therapy—using the immune system to fight cancer, as opposed to trying to kill the tumors through toxins or poison—was an idea, but it was no more on Coley’s radar than it was on Rhoads’s. Everyone was looking for Paul Ehrlich’s “magic bullet” that would hit the enemy and avoid the host. No one was looking for a simple stimulator of the body’s own natural defense system—a system that was almost wholly unknown in Coley’s time and still largely undiscovered in 1950. And the notion of checkpoints like CTLA-4 or PD-1 / PD-L1 were then as unimaginable as they were invisible.
Three: Glimmers in the Darkness
1. In terms of Western medicine, the idea that the immune system could be manipulated to fight cancer dates back to the middle of the nineteenth century, when a German pathologist named Rudolf Virchow described his view through the microscope: a slice of tumor, infiltrated with human immune cells. That was cancer (the tumor), under attack by the immune system.
2. The names for all these biological things tend to get made up along the way, and sometimes before anyone really understands exactly what they’re naming, which can make them seem unnecessarily complicated later. For example: the stuff that isn’t blood cells in the bloodstream is called lymph. That amounts to the white blood cells and fluid. The B and T cells within that fluid became lymph cells, or, with the Greek root for “cell,” lymphocytes. Now that refers to both B and T cells, the cells of adaptive immunity.
3. Vaccines have been used ever since Edward Jenner first demonstrated that the immune system could learn and remember. Vaccines safely introduced the body to the unique proteins of a disease it had never encountered before, resulting in immunity. It took several generations to understand how that happened, but even in the eighteenth century it was clear that something in the blood, a few weeks after inoculation, remembered, recognized, and attacked the disease that had been introduced. These discrete chemical bodies worked anti the foreign proteins, so they were called antibodies.
4. Biologists knew that these B cells hadn’t just been born in the bloodstream. They came from somewhere, maturing somewhere else in the body before migrating to the bloodstream. That place was located in birds before it was found in people. In birds, which have hollow bones, these white blood cells mature in a sack-like organ wonderfully named the “bursa of Fabricius.” B cells are Bursa cells.
5. Three billion might seem like a lot, until you realize that to be fully prepared for everything, you need to have 100 million different flavors of antibody, made by 100 million different variations of B cells. That means that when a random B cell does happen to find its antigen match in some bacterial invasion or viral swarm, there are only about fifty other B cells with that antibody to join the fight.
6. David Masopust, Vaiva Vezys, E. John Wherry, and Rafi Ahmed, “A Brief History of CD8 T Cells,” European Journal of Immunology, 2007, 37:S103–110.
7. J. F. Miller, “Discovering the Origins of Immunological Competence,” Annual Review of Immunology, 1999, 17:1–17.
8. There would later be found a third type of T cell, which in this metaphor would be something like a referee, regulating immune response and blowing the whistle to stop play and make sure nothing gets out of hand, since “getting out of hand” in the T cell world is dangerous. These regulatory T cells are called T regs.
9. In this ecosystem, cytokines communicate between different immune cells; see the earlier discussion of macrophages. Just to confuse the terminology further, for a time cytokines were called, as a class, “interleukins,” either type 1 or 2. They’re not all referred to in this way anymore, but we still have all these names kicking around, and so some of the cytokines are still named interleukins and given numbers. But they’re all still cytokines.
10. Burnet Macfarlane, “Cancer—A Biological Approach,” British Medical Journal, 1957, 1:841.
11. L. Thomas, “On Immunosurveillance in Human Cancer,” Yale Journal of Biology and Medicine, 1982, 55:329–333.
12. Those may include the odd patient in literature going back to Pharaoh Djoser’s physician Imhotep. The Ebers Papyrus, ascribed to the physician Imhotep in 2500 BC, advises for treatment of tumors “a poultice, followed by incision,” a course of treatment that induced infection. There is some speculation that this treatment may have brought on an occasional immune response like that witnessed by William Coley. The Papyrus Ebers: The Greatest Egyptian Medical Document, trans. B. Ebbell (London: Oxford University Press, 1937).
13. In Europe, records from the thirteenth century describe something similar in the life of a wandering monk named Peregrine Laziosi. He traveled rough, proselytizing and saving sinners as he went. His legs were often sore—the lot of a wandering monk—but at some point he took note that his lower leg was swollen, and the swelling continued to increase. Soon, a mass began emerging from his tibia. Physicians were consulted and determined it to be a malignant cancer, for which the only treatment was amputation of the leg.
Like many patients, Laziosi heard the physicians’ advice and failed to follow through. He continued wandering, the sarcoma continued growing. Eventually the cancerous mass burst through the skin, and the wound festered with infection. “Such a horrible stench was given off that it could be endured by no one sitting by him” (Jackson R. Saint Peregrine, “OSM—the patron saint of cancer patients,” CMAJ, 1974, 111). But in time his fevers broke and his tumors, remarkably, seemed also to be melting away. Several centuries later the Vatican canonized Laziosi as “St. Peregrin,” the patron saint of cancer patients. Where the pope saw a miracle, others saw a potential therapy.
14. Not his real name.
15. According to D’Angelo’s file, that was in 1957. He returned to the VA hospital five months later like Marley’s ghost, telling his freaked physicians he felt fine. Instead of dying, D’Angelo had thrived. He’d gained twenty pounds. He was working. He had a story but no explanation. It was amazing, what some might call a miracle. But his doctors were sure he was still going to die.
Sometimes cancer does that, growing without destroying the major organs, acting more like a parasite than a disease. It could remain that way for years before it spilled over and became deadly. His physicians assumed it was only a matter of time before reality reared its head.
A year had passed, then another. But when D’Angelo returned three years later with a new lump behind his ear, it was assumed that this was it, the other shoe dropping, statistics borne out. The lump was surely the same metastatic cancer. It must have filled his body and was now pushing the bounds of that body, visible even to the naked eye. This time, his physicians didn’t bother opening him up or cutting it out. Once again, D’Angelo was sent home to die. And once again, he didn’t.
16. Steven A. Rosenberg with John Barry, The Transformed Cell (New York: Putnam, 1992).
17. As a surgeon he was aware of a case where cancer had seemingly spontaneously arisen in a patient with a suppressed immune system, after he received a kidney from a donor who had gone years without showing evidence of the disease. That recipient had beaten cancer, once his immune system was unsuppressed. But this was different.
18. Our bodies were in a “constant struggle for survival and… under constant attack from foreign invaders such as viruses and bacteria,” and usually the cells of the immune system recognize them as foreign and eliminate them. Rosenberg, Transformed Cell, p. 18.
19. The extraordinary move from resident to chief of surgery rubbed some of the staff the wrong way, and some referred to him sarcastically as the “boy wonder” or even “Stevie Wonder”—which Rosenberg didn’t totally appreciate because he was thirty-four years old and had a family, including two children.
20. Including Dr. Donald Morton, who had been at the National Cancer Institute just prior to Rosenberg’s arrival.
21. He was aware of Coley and his toxins, and while he didn’t have much intellectual interest in his approach, other contemporary immune researchers whom Rosenberg respected certainly did, including Dr. Lloyd Old, who had identified a substance made by immune cells that he believed had been part of the toxin’s mechanism of action (a cytokine he called “tumor necrosis factor,” or TNF).
22. Bacillus Calmette-Guérin, or BCG, is a tuberculosis vaccine approved for use as an immunotherapy in bladder cancer.
23. This was Rosenberg’s statement, and not as subjective as it might seem here. He pointed out that part of the scientist’s job is to sort signal from noise in the scientific literature (Rosenberg, Transformed Cell).
24. This was based on work by the English scientist M. O. Symes and on discussions with his friend David Sachs.
25. Rosenberg identified her as Linda Karpaulis.
26. Francis W. Ruscetti, Doris A. Morgan, and Robert C. Gallo, “Selective In Vitro Growth of T Lymphocytes from Normal Human Bone Marrows,” Science, 1976, 193:1007–1008.
27. Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
28. Rosenberg would write, “Ten months after Gallo’s paper appeared Kendall Smith, who was at Dartmouth and on his way to becoming the word’s expert on IL-2, and his post-doctoral fellow Steve Gillis published an article in Nature… about using IL-2 to grow mouse T cells.”
29. Several other researchers had also found or described what would be realized to be IFNs previously, but this group is justly credited with the publication: A. Isaacs and J. Lindenmann, “Virus Interference. I. The Interferon,” Proceedings of the Royal Society of London. Series B, Biological Sciences, 1957, 147: 258–267.
30. The chemical messengers are cousins of hormones, the chemical messengers that quickly and powerfully communicate across the blood-brain barrier and unleash a menu of cellular changes, depending on the cytokine in question. In the ’60s and ’70s the discovery of even more of these messengers of immune action and inflammation resulted in a sudden surge of new chemical names and an alphabet soup of acronyms, so many that, as a group, they came to be referred to derisively as “leuko-drek,” a blah-blah of immune scientific jargon. Adding to the confusion was the decision by some young immunologists at a conference to take it upon themselves to simplify the nomenclature by referring to all immune hormones as “interleukins” of either type 1 or 2 (depending on the major histocompatibility complex, or MHC: a region of chromosomes that includes a complex, or specific and unique, arrangement of genes that are involved in antigen presentation). That didn’t stick entirely (though it has somewhat, hence the confusion). As a class they are now referred to broadly as cytokines.
31. Including into cellular communication, and how signals are translated from the outside of a cell to in, from receptor to nucleus, as shown by the work of James Darnell, Ian Kerr, and George Stark, and others. Ten years after its “penicillin” moment, it would be discovered that interferon alpha and beta were important aspects of immune signaling and stimulation, including the stimulation of T cells. The “failure” of interferon is a misperception that, like many false stories, is far more memorable and harder to dislodge from the truth. And the truth is that IF is now approved as a therapy for use against several human diseases, including hairy cell leukemia, malignant melanoma, hepatitis, genital warts, and others, and it continues to intrigue researchers.
32. For natural IL-2, near twice that for the recombinant form.
33. As an aside: the classic nineteenth-century experiments that resulted in the theory that inherited traits are carried on discrete genes owes much to the fact that Gregor Mendel was not allowed to breed rodents in his monastery, and so he performed his famous experiments using peas. By chance, the genes coding for pea color and the smooth or round surface characteristics happened to be on separate chromosomes, thus enabling the observations leading to Mendel’s hypothesis.
34. In addition to a distinguished career in cancer, Dr. DeVita’s biography mentions that his son Ted was diagnosed with aplastic anemia and served as the inspiration for the character played by John Travolta in the 1976 made-for-TV movie The Boy in the Plastic Bubble.
35. A follow-up to Rosenberg’s NEJM paper, in the Journal of the American Medical Association, provided a clearer picture of those side effects. Of the ten patients in the follow-up cohort, eight ended up in the intensive care unit. Those side effects included “leaky” blood vessels resulting in extreme fluid retention and grotesque swelling in a very short amount of time, dangerously high fever, racking chills, platelet counts that barely registered, and other various issues that required cardiac catheters, transfusions, antibiotics, and dozens of other secondary medications for this “natural” approach that used Mother Nature’s own signaling chemicals and our natural immune defense.
36. Rosenberg, Transformed Cell, p. 332.
37. Follow-up NCI-funded trials of Rosenberg’s IL-2 results at half a dozen medical institutions around the country failed to replicate his success. There’s little doubt that Rosenberg achieved the results his papers stated, and several of his former colleagues I interviewed referred to him as perhaps “the most ethical man” they knew. But the inability of other physicians to replicate Rosenberg’s successful results in patients gave many, even oncologists who were immunotherapists, pause when considering IL-2 therapy. A patient’s best option, several told me, was to try to get cared for by Dr. Rosenberg personally.
38. Dr. Jedd Wolchok at Memorial Sloan Kettering Cancer Center reduced the approach thusly: “You start by identifying the molecule that’s gone wrong, the one that’s causing the cancer cell to do the most recognizably ‘bad’ action—which is to just continue to make more of itself. And then you interfere with that; you short-circuit the pathways, you block it, and make it stop doing that thing.” Perhaps the first example of this is the Philadelphia chromosomes, in chronic myeloid leukemia. Another is the BRaff mutation, in melanoma.
39. At the University of Washington, Dr. Philip Greenberg led the conceptual advances of this therapy and was the first to show it could kill cancer in mice. In the following year Rosenberg’s lab would work with the T cells that leave the bloodstream and infiltrate tumors (tumor infiltrating lymphocytes); his lab would soon be involved with CARs as well.
40. Rosenberg had used the T cell growth drug IL-2 and showed that by overwhelming stimulation of the T cell army, and overwhelming numbers of T cells, they could push it to kill cancer, sometimes, in some patients.
41. Like the four humors that governed medicine through the Middle Ages, or the nineteenth-century vitalist’s belief that living beings contained an ethereal life spark.
42. The modality of virus-related cancers is similar to genetically linked cancers. The virus does not produce the cancer, but it reprograms a cell’s DNA to a state where it takes fewer new mutations to line up just right so that a cancer is the outcome. You can think of it like a slot machine, and a virus or certain genetic conditions as two cherries fixed in place on the dials. The likelihood of that machine hitting three cherries is much greater than in a “normal” machine.
Four: Eureka, Texas
1. On leaving Alice, Allison says, you know, he liked it OK, it was small and he was happy, though—and here he draws a breath, careful, he knows how it can come across—he didn’t want to be like every other guy from there. Alice was a dot on a local map an hour west of Corpus Chisti, forty-five minutes if you were hauling it, and it was small-town Texas, a lot of it good—good folks, good farms, a good upbringing and jobs, being close to the air force base. His father had earned his wings as a flight surgeon in the reserve there, and he translated that to becoming the local physician, but his people had been from Waco, where they’d owned a shoe store. He’d made a leap to Alice. Jim wanted the next leap. He wasn’t going to be happy there. He’d grown up in a small town, he loved it, loved the place and the people as you can only love what you’re from. And knew them, too, as only a local boy can know a thing. And, he says, he didn’t want to just be that guy, like every other guy.
There was nothing wrong with it. He did like the football, just not playing it; he liked the small-town vibe, just not being stuck in it. He was a reader, a tinkerer. He had a curiosity and an idea about himself, too, not necessarily precocious, more like potential. The family garage became a lab, the woods a place to test homemade black-powder bombs, the ponds a source of dissectible amphibians. If you talk to most research scientists, have a couple beers with them, you realize they all were a little on their own, and many made homemade explosives; it’s normal, young-scientist stuff. And if that made him a weirdo in meat-and-potatoes Texas, so be it. There were three boys in the house anyway, and the two older ones more than made up for it. His dad supported him when he lobbied to take an advanced high school biology correspondence course through the University of Texas, rather than suffer through a senior year of biology taught without evolution. And then the following year he turned sixteen and graduated, and he was gone for good. Austin was the center of the local freak scene, and it had a great university, too. But on both accounts, eventually he found out Berkeley was greater and freakier than almost anywhere.
2. These were the peak years, when it was still wide open, a little university town just beginning its metamorphosis into the freak capital of a cowboy state.
3. Of course, Jim Allison wasn’t alone in that. These were Austin’s boom days. The town had been a tiny university town until the baby boomers graduated high school. Smaller than big cities like San Francisco, which received and fostered the flower power of the ’60s, landlocked and deep-Texas Austin became the repository of the local version, still Texas enough to two-step, hippie enough to do it stoned, and close enough to the university to ensure a steady flow of bright young things with an eye on the future. For many, that future no longer required heading to bigger cites on the coasts, or overland to Dallas or Houston. It could be found right there in Austin, where Texas Instruments, Motorola, and IBM has recently relocated their manufacturing.
Of course, it didn’t hurt when the voting age—and the drinking age—was lowered to eighteen and the closing hours were extended to 2 a.m. Politically empowered, legally drunk teenagers could thus romp past midnight in the freak capital of a cowboy state, and a music scene quickly sprang up to provide the soundtrack. If you sold beer and had a surface flat enough to put a bar stool on, you were a music club.
4. “I was trained in biochemistry, so I was working with asparaginase, which is this enzyme that can deplete your plasma of asparagine, which many leukemias need to grow. They can’t make their own. It’s still used to induce remissions in childhood leukemia, but it doesn’t cure anybody. In mice it cured the leukemia. I was trying to work on making it work better. I began to read about this immunology stuff. I took a course and I got really excited and interested about it. Just for the hell of it one day, I cured mice with this enzyme of this leukemia that they had.”
5. When injected into the mouse, the enzyme broke down the fuel. As a result, the leukemia was starved and the mouse cancer cells died. Then those cells, like all cells that die in the body, were cleaned out by the roving, garbage-eating cells of the innate immune system, the macrophages. Allison wanted to know how they worked, too—how all of it worked, really.
6. His voice has the distinctive music of the back country, a little extra beat put into the last word, seemingly no rush to move to the next one, except when that beat is over he moves on quickly, where he was going all along.
“I was lucky enough to be at one of the very few universities not connected with a medical school that even had anything on immunology,” Allison says. He was training to be a biochemist, but the work had sparked an interest in another aspect of biology—the immune system—and one of his graduate professors, Jim Mandy, offered a course. Allison jumped at the chance, “and I was just fascinated by it.” His professor lectured on the newly discovered T cells. “He taught the discovery,” Allison says. “He gave the lecture. But after hours you go see him in his office, he’d tell you he didn’t really believe it was true. He was an antibody guy.” What bothered Allison’s professor—and a great many others in immunology—was that T cells seemed too different from B cells to be part of the same system.
B cells didn’t kill disease directly; they made antibodies, and the antibodies marked the disease to be killed by the innate immune system. That had been immunology for years, and the direction of research was to continue to clarify that scenario. “But these T cells came along and people were saying, ‘Well, these work differently, by killing infected cells directly,’” Allison says. Adding T cells to the B picture seemed too complicated. Evolution tends to be a conservative force, using the same biological processes again and again, repurposing and building on the biology it already has rather than starting from scratch. If the immune system was complicated, those complications were most likely to have grown out of common roots and to utilize similar mechanisms. It was almost beyond imagination that nature would have evolved two totally different types of systems with overlapping jobs in the same organism. “He taught it anyway, but then I’d go and talk to him in his office and say, ‘Dr. Mandy, why don’t you believe T cells kill infected cells?’ He’d say, ‘Well, I just don’t know, it just seems too weird, you know?’” It was as if each of our kidneys removed toxins from the blood in completely separate ways, with no relation between the two. Allison thought it was weird too, good weird. He wanted to “check it out,” learn more about it. “It was a fantastic time in science,” Allison says. “Immunology had just always been this poorly understood field—I mean, everybody knew we had an immune system, because there were vaccines. But nobody knew much about the details of anything.” He’d already hit the ceiling in the only immunology class available in Austin.
7. The macrophages and dendritic cells (biologists just say “antigen-presenting cells,” or APC’s) act like a living billboard showing the latest winning lottery numbers, in the form of unique samples of disease antigens. Every one of the billions of adaptive immune cells was born with a different lottery ticket. Sooner or later the number hits: the B or T cell happens to randomly match exactly with the antigens being reported, and they start multiplying into a clone army of themselves, all with the same winning ticket against the disease being shown, and bingo, adaptive immune response is initiated.
8. “It was kind of disappointing,” Allison says. He had wanted to go somewhere “first-rate” for his immunology education. “But I was just doing biochemistry again, purifying proteins and sequencing them and all this stuff. The older guys would just have you doing this grunt work, everything else they called model making, as in, ‘don’t make models, don’t think, just do the work!’ So I said, if this is science, you can have it, I’m going back to Austin! But at the time I was in San Diego. I was married and I played with a country and western band a couple nights a week. I had a pretty good time.
“Remember Spanky and Our Gang that did that song, ‘Like to Get to Know You’ and all that stuff? I played with a band that opened for them one night and actually sat in with Spanky McFarlane.” A longhair PhD harmonica player was cool, an easy fit in the music scene.
“Well, I played at this place called the Stingray. We had a band that played. It was called Clay Blaker, the Texas Honky-Tonk Band. I had a day job. They didn’t. Everybody else in the band would… I’d just hang out and play, you know, a couple of sets, maybe, or half a set every now and then, or something. I got to know them really well. Through them I got to know other people. I was pretty popular as a harmonica player for up-and-coming singers that would want to play at open mic night and stuff like that. Our band got pretty famous in what was called the North County. This was up in Encinitas, California. I got to see a side of life that I’ve seen a little bit when I was growing up in Alice, but you know. I mean, pretty rough and tumble.”
At the time, Jim was married and working seven days a week, and, as always, playing hard. “We played every Tuesday night and a lot of Friday nights and sometimes nights in between.” It was rowdy sometimes, playing harp in the country-western dives in the sticks. “People don’t realize, that part of California is pretty redneck,” Jim says.
“There were fights pretty regularly, usually it’d start because one cowboy that’s doing a two-step would swing too widely and bump into a guy and the guy would say, ‘Don’t do that again.’ Then, that’s just the way the guy danced, you know? So it happened again. Add beer and a crowd and pretty soon…
“Actually, it was this guy named Luther, he was one of the guys that came to see us all the time. We really liked him. That’s who he was. He was just this big, gangly guy that danced big. There were some other guys from this other club that heard us play at another club, so they decided to come to our club to see us. It was almost like a gang or something.
“After three or four times one night, the guy slams into Luther. You know, Luther was everybody’s friend. I was up on the stage and there was a guy there, it was so crazy, it was a guy that had just gotten… He was pretty rowdy, but he had spent some time in jail for stealing horses. Anyway, he was there and he’d broken his arm somehow and it was in a cast. He came running up to this guy that had hit Luther and, you know, hit him with that cast and the guy just went parallel to the floor. I was playing, you know? The guy goes parallel to the floor and I jumped out of the way, you know? The guy jumps up on the stage and now it’s like something out of a Western.
“I went, ‘Whoa.’ That guy down there who I knew pretty well, but he was just going, ‘Oh, shit. Oh, shit.’ There was stuff like that. It was a lot of fun.”
One night, he tagged along to a musician’s party—crashed it, really, since it ended up being a release party for Willie Nelson’s new album, Red Headed Stranger. That led to taking Willie Nelson and part of his band to an open mic night at a honky-tonk, then back to their hotel in his faded red VW microbus.
Many years later Allison would end up standing in for Willie’s harp player. Allison is a founding member of an all-immunologist band called the Checkpoints. They really are pretty good.
9. “If I saw something interesting, you know, I’d chase down a couple of the things they’d cited and Xerox them and take them home.
“At that time, I was living in Austin. My wife worked in Austin and I was living there and commuting forty-five miles a day to Smithville. Ultimately, we bought a house in a failed development with eighteen acres of land. The lab was in a state park. It was in the woods in a clearing. I bought in the woods, about a mile and a half, because I had a motorcycle, or I’d walk sometimes through the woods. Then, I’d go back to Austin on the weekends just to party.”
He didn’t have time to gig out then, he was too busy, but he could still catch Willie Nelson or Jerry Jeff Walker at the Armadillo Worldwide or the Soap Creek Saloon.
10. Soon after Allison joined the team, the president of MD Anderson left. “The new guy came in and didn’t really know who we were.”
11. By then it had been shown that there’s major histocompatibility complex (MHC) restriction. T cells don’t recognize just an antigen; they recognize it in the context of these MHC molecules. The MHC molecules are a distinct arrangement of proteins that can be thought of something like blood type, in that we’re all born with one or another of a few flavors, genetically determined. Not every person shares the same MHC, but all the cells in a person’s body share the same group. The MHC complex is sort of like a tribal mark or signature on every cell’s surface, and it serves as a basic but effective factor that allows the immune system to be a better shepherd, to keep track of what is us, and to recognize what is a foreign invader. (It’s also what needs to “match” so that tissue or bone marrow transplants won’t be rejected.) Allison had been studying and working with experiments involving MHC molecules in his lab at Smithville, and he’d been obsessively following the latest developments in the immunology journals. He knew the MHC was an important factor in how this mysterious T cell receptor worked—a factor other researchers seemed to be ignoring.
Jim had a different kind of molecule in mind as the T cell receptor, and he’d thought of a different sort of experiment to find it.
12. Finding it was like looking for cilantro in a field of parsley—in the dark.
13. People were looking for immunoglobulin chains that were made by T cells.
14. Including immature thymocytes.
15. The experiment staked a solid claim, but it wasn’t absolute proof that Allison had found the holy grail. His experiment was just that, an experiment, providing results, and Allison didn’t have the sort of pedigree that provided him benefit of the doubt. “Nobody believed it because I was this guy in Smithville, Texas, you know?” Allison makes clear that whatever his experiment did, it didn’t “prove anything. Science rarely, if ever, proves something, but good science can present good data, and good data can strongly suggest.”
16. Academic papers follow a standard, dry format that lets the data speak for itself. It’s in the “discussion” section at the end where authors may speak more personally, if imprecisely, about further implications that might be suggested by the data. Allison’s paper, titled “Tumor-Specific Antigen of Murine T-lymphoma Defined with Monoclonal Antibody,” followed this format. The text was dry and factual and made no claims, carefully explaining what he’d done without mentioning “T cell receptor” at all. He made up for it in the discussion.
17. Like Davis, Tonegawa had been working on unraveling the genetics of immunology since the mid-1970s, and Tonegawa had been first to identify the gene in B cells that allows them to make millions of varieties of antibodies to meet a wide diversity of pathogens—a goal that Davis had also been working toward.
18. Chien et al., “A Third Type of Murine T-cell Receptor Gene,” Nature, 1984, 312:31–35; Saito et al., “A Third Rearranged and Expressed Gene in a Clone of Cytotoxic T Lymphocytes,” Nature, 1984, 312:36–40.
19. Davis would later recount for a reporter for Stanford Medicine magazine that the editor of Nature had called him to recount how unhappy Tonegawa had been at this “divine justice,” but he said his MIT competitor had been magnanimous in defeat.
20. This was the sort of thing Allison dreamed of as a kid. Was it for Mom? Jim says no, but that’s a maybe. Maybe everything we do is for Mom, one way or another. If anyone knows, it’s certainly not the doer. But it’s true that he had that experience and it stuck with him, just eight or ten as he was, and so, maybe he wasn’t eight or ten—man, it gets mixed up, you start talking about your mom and dad.
What he knows was, she died. He was there, he didn’t know what the disease was or how you fight it, then later, he learned what the disease was, and that nobody had much useful to say about fighting it, and he thought: Fuck this. I’m going to do something.
21. Justifying himself in front of fifty of the top scientists in the world was no picnic, and even the memory of those visits, which were timed to the second by stopwatch, still knots his stomach. “It was pretty bad,” he says. “Sometimes the night before I’d just be in the bathroom throwing up.” But the trade-off was, Allison finally had all the resources he could ever need to get down to work.
22. “It wasn’t my idea,” Allison clarifies. “It came from a guy named Ron Schwartz with NIH and a postdoc in the lab, Mark Jenkins. They showed that just the engagement of the antigen receptor itself was not enough to turn on a T cell. And it showed increased deselectivity.” See Mark K. Jenkins and Ronald H. Schwartz, “Antigen Presentation by Chemically Modified Splenocytes Induces Antigen-Specific T Cell Unresponsiveness In Vitro and In Vivo,” Journal of Experimental Medicine, 1987, 165:302–319.
23. Allison had seen it himself, and experiments at the NIH had proven it. Allison had spent years on the biggest, most complex jigsaw puzzle in biology, and this new revelation was asking him, and everyone else in biology, to rescramble the pieces. Which, Allison thought, just made the whole thing “more interesting.”
24. “Only certain cells could do that. Later on it turned out they were dendritic cells that Ralph Steinman [whose lab included a young Ira Mellman] got the Nobel Prize for a few years ago. So we did a lot of work showing where they came from, never could show what they did though.”
25. “Anyway, then I got into the idea of combination-stimulation, and a second signal came along. So we had the lab dive into that, so we came up with the whole idea that CD28, I mean there is a molecule that a lot of other people worked on. Yeah, so a bunch of people, Jeff Ledbetter, and Peter Lindsley, Craig Thompson, and some other people have been studying. They made an atom out of this thing called CD28, and it would partially activate T cells. There was a lot of literature that it would do things in humans but this issue of a second obligatory signal, their work really didn’t answer it. Partially because you really can’t, it’s hard to do with human cells, because humans don’t have a lot of, one reason, humans don’t have a lot of naïve T cells. Because, we’ve had so many infections overall, so in your blood most of the cells are there looking for something to do. We’ve seen it before where mice, we keep them clean.”
26. “A guy named Jeff Ledbetter had really been studying [it] for a long time, along with Craig Thompson and Carl June and Peter Lansing and others,” Allison explains. Allison had a couple reasons to think it might be the costimulating signal.
27. Allison did the experiments, and they worked. “So, it’s officially necessary to give that second signal,” he says. And that seemed to be that. He published the paper. “I was really happy,” he says. “I’d been working on it for like three years” he says, “just thinking about it—everything moves slow.” But Allison was a researcher. And thinking about CD28 had led him to thinking about the unique problem of cancer. It didn’t get attacked by T cells. Most scientists assumed it was because this was a self cell, too similar to normal healthy body cells to be recognized by the immune system. But Allison now had different thoughts. And as it happens, he was having them at the very moment when he was doing basic research in a well-funded cancer lab. “It occurred to me that, since tumor cells didn’t have those [CD28] molecules, maybe they’re invisible for the immune system, even though they have tons of antigens. The immune system can’t see them, because they can’t give that second signal.”
28. “So that was a science paper, but all the time that was going on, when we cloned mouse CD28, we didn’t first identify the molecule. Other people did, even cloned it, but the human one. We cloned the mouse T and studied it and showed that CD28 was this costimulatory molecule.”
29. Signaling proteins have an inside-the-cell and an outside-the-cell aspect; they stick out of the surface through the cell membrane like a carrot sticks up from the ground. The outside part interacts with the outside world and receives the signal. That signal travels through the protein to the inside of the membrane and the aspect of the signaling molecule that is inside the cell, which is where the action happens; then it initiates gene expression, a sort of “reaction” to the signal. What Allison and Krummel found was a molecule in the gene bank that had an exterior component—the carrot green—that was “like 85 percent identical” to the exterior signaling portion of CD28. That family resemblance might have been coincidental, but Allison felt that the better bet was that it meant the two signaling proteins were in fact closely related evolutionarily—and did similar things. “To me everything comes back to evolution sooner or later,” Allison says.
30. “This guy Chip Holstein had cloned it,” Allison says, which allowed researchers to study it further. “Didn’t know what it did, just knew it wasn’t in naïve T cells that got turned on.”
31. “CTLA-4 comes from this guy, Pierre Goldstein from France, who was again doing subtractive hybridization to find things that were expressed only in T cells. He took T cells and subtracted RNA that was in B cells as well and looked at what was left. The fourth thing he got was CTLA-4, or cytotoxic T-lymphocyte-associated antigen protein #4. That’s where it came from, and it’s a complete misnomer because it turns out, it’s in all T cells, not just CTLs (killer T cells). It’s also in helper cells. It’s in every T cell after they get activated. But I like the alliteration of that, CTLA-4.” It’s also called CD152.
32. Linsley et al., “Coexpression and Functional Cooperation of CTLA-4 and CD28 on Activated T Lymphocytes,” Journal of Experimental Medicine, 1992, 176:1595–1604.
33. Krummel designed a model to press both pedals and tried it in animals, then dialed the mix of gas and brake, CD-28 and CTLA-4, like a new driver. Demonstrating that you could drive T cell response up and down in animal models as he’d predicted on his spreadsheet, made with an early version of Excel, really drove home that they were looking at what they’d suspected. “Jim was really a hands-on PI at that time,” Krummel remembers. “I think he taught me how to inject my first mouse.” Krummel says Allison’s attitude for his chosen postdocs was essentially Trust your instincts. Try things. He also paraphrases this as Fuck it, try it. Krummel tries to instill that spirit in his students as a professor of pathology with a laboratory at the University of California, San Francisco. “I didn’t even know anything and was allowed to throw antibodies into mice,” Krummel says, by way of a tribute to the culture of Berkeley at the time and Allison’s lab in particular; certainty in science is often anathema to pure exploration.
34. The belief at the time was that T cells were calling the shots in terms of this immune response. It is now believed that macrophage cells from the innate immune system—those large, hungry “garbageman” cells that gobble up the detritus of the body help regulate immune response by means of cytokines. It’s also now understood that T regs, which had not been discovered at the time of this CTLA-4 work, are the cells primarily expressive of CTLA-4 and so play an important part in down-regulation of activated T cells.
35. “Jeff Bluestone, who was at the University of Chicago just about the same time, independently did the same thing,” Allison says. Bluestone was an immunologist (he’s now the CEO of the Parker Institute for Cancer Immunotherapy) and his lab was trying to utilize this newly discovered immune brake to prevent rejection in organ transplants and autoimmune-related diseases—issues that were widely accepted as being within the immune system’s wheelhouse.
The majority of cancer experts and immunologists believed that cancer had nothing to do with the immune system. Allison, meanwhile, was a biochemist who had wandered into immunology, and, in a pattern that repeats itself throughout the history of advances in cancer immunotherapy, he wasn’t aware enough of the battles between believers and nonbelievers in cancer immunotherapy to realize that he’d casually stepped across the battle line. The next step in his experimentation was more controversial.
36. And so, even as he had his eyes fixed on the road ahead, doing pure science on T cells, that thought was always traveling with him in the passenger seat. He describes it sometimes in terms of a Jerry Jeff Walker song about a cowboy cruising down the highway with one eye on the road and one eye on the gal next to him. Even as he was driving, he’s always angling on when he can pull over.
37. Allison knew cancer. He knew it as a kid, though they didn’t call it that. Cancer wasn’t a word you said then, it was a dirty thing, a curse, the C word. You didn’t say it, but Jim could see it. It was in his mother’s eyes, the way her dress hung as she set the table, hiding her exhaustion in silence and forced smiles. That was Texas and she was cow people, tall boots and tall cactus and family stories of the Chisholm Trail. Cow and horse people, true Texans, and not given to complaining, not even with the disease progressing unchecked or her pale skin flushed from the radiation burns, the only way science had to arrest it. That was how it was, three summers and getting worse but not getting talked about. Jim remembered one summer day when one of the adults came to find him and told him he needed to go home, now. Five decades later he can still feel her hand go limp and the light go out; that stark, awful moment when it changed still brings water to his eyes. So was this work, this needling thought in the back of his mind, for his mother? Maybe everything we do is for Mom, one way or another.
“Well, I didn’t know why she had it, I just knew she was sick. Nobody talked about cancer, nobody said cancer, nobody in my family, I didn’t know what was wrong with her. I didn’t know what cancer was. I just knew my mom was sick. One day, I was headed to the swimming pool with some friends and somebody came running out of the house and said, ‘No, you can’t go. You have to come back and be with your mom.’
“And I still didn’t know what it was. I mean, I was holding her hand when she died. And I didn’t know what it was, I just knew she was dead. I had to put it together later because I was just too young to know. It pissed me off, though.”
Alice wasn’t a big town, and the Allisons lived on the edge of it. They were already on the edge of outside. Jim’s mother’s death pushed him over that edge. He spent a lot of time just walking, not knowing here he was going, kicking the dirt, keeping his feet moving so his head couldn’t think too hard about what had happened. That was how he found the settlement.
He’d stumbled into it by accident, a decaying little ghost town in the woods. He was picking through the woods, trying not to think but thinking anyway, and suddenly he realized, this was a place. Somehow, it still was. Here, among the wet leaf floors and creeping walls of moss, watched only by the damp eyeholes of collapsing root cellars and the ghosts of failed generations of dirt farmers, Jim Allison dreamed of something bigger. Genetics, environment—the causes of cancer mattered, from a scientific perspective; everything mattered. From a personal perspective it didn’t matter worth a damn. Cancer was just true, whether you understood it or not. You’re here and you’re gone, like these families, like this town, falling back into dust. It was his mother gone to that thing. Later it took his older brother too, prostate cancer this time, and shortly after, when Jim got the diagnosis of the same thing, he just said, “Fuck it, cut it out.”
38. In fact, it would make it through, in 2011. Once approved by the FDA it was marketed under the trade name Yervoy; it would cost patients $120,000 for a full course.
39. Allison and Krummel both appear on the provisional patent application. Allison’s postdoctoral fellow Dana Leach would also be added.
40. Now known as the Geisel School of Medicine. The essential work of Drs. Nils Lomberg and Alan Korman in the development of antibodies for both anti-CTLA-4 and PD-1 deserves its own chapter.
41. These mice had been genetically engineered; their immunoglobulin (antibody protein type) genes had been replaced with human immunoglobulin genes. As a result their immune response against a foreign protein (in this case a human CTLA-4 receptor) produced antibodies made of proteins that wouldn’t look foreign to a human, and those antibodies could go into humans without triggering an immune response against them.
Five: The Three E’s
1. It’s important to emphasize that Allison consistently makes clear the contributions, many of them essential, of those in his lab. He names Dr. Matthew Krummel in particular, and is even more clear on the fact that Dr. Jeff Bluestone—who at the time had moved from the University of Chicago to the University of California, San Francisco—had simultaneously discovered that CTLA-4 was a down-regulating signal, an immune brake rather than a gas pedal. Bluestone has been consistently and publicly recognized for this work, but because he applied it to further research on the down-regulation of immune response, rather than blocking that down-regulation with an antibody and testing it against cancer, his name is not as widely associated with the breakthrough in cancer specifically. Bluestone was named the president and CEO of the Parker Institute for Cancer Immunotherapy, a job that had him at the center of funding and coordination of the efforts of thousands of scientists and researchers around the world.
2. Dr. Old’s 2011 obituary in the New York Times credited him as being essential to an approach to cancer “also known as biotherapy.”
3. He was an heir to Coley, personally championed by Coley’s daughter, and, somehow, also friendly to the cancer gods at Memorial Sloan Kettering Cancer Center, where he maintained a lab and office and held the William E. Snee Chair of Cancer Immunology.
4. As frequently you’ll hear him referred to as “the father of tumor immunology.” In addition to articulating the concept that cancer has unique molecular “ID tags” (antigens) that should make it a unique target for the right kind of immune response, Old was responsible for such major immunological advances as the discovery of a legitimate bacterial treatment heir to Coley’s Toxins, in the form of bacillus Calmette-Guérin, or BCG; it was one of the first immunotherapies approved by the FDA and is still effective against some forms of bladder cancer. He believed in an immune-based interaction between cancer and the immune system, and kept the field alive during its darkest days. He was a remarkably broadly educated man, a concert-level violinist, an accomplished immunologist, and the heir apparent to the torch borne by William Coley. He was also the founding scientific and medical director of the Cancer Research Institute, founded by Dr. Coley’s daughter, and he held this position for more than forty years. By reputation and as relayed through dozens of interviews, Dr. Old was part Osler, part Huxley, and all mentor. Unfortunately Old died of prostate cancer in 2011, at the age of seventy-eight. His death came just before the approval of the first checkpoint inhibitor.
5. Even in the darkest hours, when researchers had mustered little solid scientific data to support the theory, Old remained an unapologetic believer in the interaction of cancer and the immune system, and he worked to popularize and explain those ideas through articles in both scholarly peer-reviewed scientific journals and the popular press; his 1977 Scientific American article, rakishly titled “Cancer Immunotherapy,” lays out the basic concepts for a lay audience.
6. Robert D. Schreiber is the Alumni Endowed Professor of Pathology and Immunology at Washington University School of Medicine. Bob was also kind enough to remember me. He’d have had every right not to. I’d been sitting at the bar of the Copley Hotel in Boston during a typically crappy Boston winter day. There was a cancer immunotherapy conference in full, florid bloom in the surrounding conference center, and college football games on a series of distantly hung televisions. There were potted ferns, and there was an open table where I’d stopped in to say hi to Jim Allison. What Jim Allison had been talking about regarded his landmark discovery of the thing you could turn off and on in humans and cure cancer. Then Jim had introduced me to Schreiber and said, with no hesitation, “I found it, but Bob proved it.” I wrote that down and wrote down his name and about a year later finally got around to figuring out what the heck Jim Allison was talking about.
7. They weren’t mice, but they were close cousins, and you could use them in mice, so their immune systems didn’t reject the antibodies as foreign. “They were nonimmunogenic. So you could do in vivo experiments even before the days that you could easily make knockout mice,” Schreiber says. Incidentally, using Armenian hamsters was not the norm for most biologists, since mice are the usual experimental animal, the lab rat of imagination. Schreiber had first read about Armenian hamsters in a journal article. He and his colleague, Kathy Sheehan (Kathleen C. Sheehan, PhD, cohead of the Immunomonitoring Lab and assistant professor of pathology and immunology), tracked some down at a lab in Brandeis University, where a researcher had been using the same inbred population for so long that he’d essentially created a standardized genetic population. The outcome was that they didn’t produce antibodies in mice—which turns out to be critically important here, because we now realize that, especially in terms of studying immune response, what works in mice does not always translate to humans, and vice versa. Specifically, much of cancer immunotherapy does not work in mice—which turns out to have been yet another hidden wrench in the gears of scientific progress in that field.
On a related note, penicillin, which has saved many millions of human lives, is fatal to mice. Luckily, penicillin was discovered and quickly tested directly in humans as part of the war effort. If it had been subjected to the usual protocols for FDA approval and gone through mouse models before human trials, that breakthrough might not have been recognized, and many millions of lives would have been lost.
8. The work might sound like developing a key and throwing it toward a lock, and that’s not totally wrong, except for the seeming randomness of the process. Here, you make a key you think fits a lock, and you put the two together in the lab. If the lock fits, that proves something—but what does fits mean? As always, the metaphors help, but sometimes they confuse as well. For example, you might think that a “fit” between a key and a lock would turn the lock mechanism and activate the lock. In fact, it’s something like the opposite. If the key fits the keyhole, it blocks the keyhole; it prevents the lock from functioning. The metaphor is more like a parking space. If you block it, nothing else can use it. Bob’s lab had discovered that their molecules fit the cytokine keyhole.
9. According to Schreiber’s recollection.
10. The experiments were based on a guess—or, in scientific terms, designed to attempt to refute if they could, and support if they couldn’t, a specific hypothesis. The hypothesis was that interferon gamma made a tumor look even more foreign (immunogenic) to the immune system, and therefore played an important role in amplifying the immune response. Experiments were the only way to test those guesses.
Bob thinks back on it and smiles. “I said, well, I thought—maybe there’s a sort of amplification system,” he told me. “One that happens between gamma interferon and TNF.” Bob thought interferon gamma maybe amplified the signal or the result of TNF. Maybe interferon gamma, somehow, made that tumor easier for the TNF to recognize. “So,” Bob said. “Wouldn’t it be interesting if in fact what gamma interferon was doing here is actually affecting the tumor, to make the tumor more immunogenic?”
In the chain of dominos, interferon gamma would be in the middle there, a domino that falls and hits two more. Then each of those falls and hits two. You could see it as amplification, or you could see it as a safety mechanism—this was the immune system we were talking about, the double-edged sword that fights measles and manifests as AIDS. The immune system had to be randomly ready to fight anything, including things it had never encountered. It couldn’t have a great number of random answers at the ready, of course, but it had to have at least one that could recognize the new random threat, one for each. Then it needed to be able to turn that one soldier ready to fight that random threat into a whole army. But it also needed to make sure that it fought only threats. It was about amplification and modulation; the immune system needs to have both amplification and safety in order to make an attack signal strong enough to effectively communicate the need to join the fight, but conservative enough not to cry wolf and trigger a cannibalizing attack by the immune system on its own body.
11. “It’s an inactive form of the IFNγ receptor,” Schreiber explains. “That mouse has a lot of trouble mounting cell mediated immunity. So it has a significant deficit, and by that criteria is immunodeficient.”
12. As it happens, one of the students in Bob’s lab had recently figured out a way to make a mouse that expressed a dud form of interferon gamma—meaning, interferon gamma that plugged in but didn’t turn on. They transplanted Old’s tumors into the dud interferon gamma mice, and they transplanted them into normal “wild-type” mice. Then they gave both mice tumor necrosis factor. In the normal wild-type mice, the TNF killed the model tumors. In the mice with inactive interferon gamma, it didn’t.
13. Reputable hardcore immunologists didn’t spend too much time thinking about tumor immunology. Few scientists did. As a result, the few in the field who did get results were looked at suspiciously. It wasn’t that they were considered charlatans or wizards, but their results weren’t always reproducible in other people’s laboratories.
14. Really, nothing is ever fully answered or proven; theories are supported, evidence is presented to suggest conclusions, and data suggests what we might call answers to questions. But to assume that any question is ever completely and definitively answered is to ignore the history of science.
15. Ehrlich was exceptionally prolific and is considered the father of modern immunology, among other fields. As Arthur M. Silverstein points out in his second edition of A History of Immunology, Ehrlich had worked in Robert Koch’s laboratory in Berlin, and in addition to his medical studies held a lifelong interest in the relationship between the structure of molecules and their biological function. This interest and insight on structural chemistry made him uniquely qualified to postulate the physical stereochemical relationship—and the unique binding affinity—between antigens and antibody. The fuller extension of this line of thinking—his conception of the perfect medicine—is the foundation of the mechanism of immunity, and much of our drug delivery. Ehrlich posited that if one could make a molecule or compound that was attracted only to a pathogen or diseased cell, then that molecule would serve as a guided missile—or, in the language of nineteenth-century technology, a “magic bullet” (magische Kugel), guiding any poison payload uniquely to that disease while sparing the host.
To that end Ehrlich’s lab tested hundreds of different compounds against various disease-causing bacteria. Eventually, in variant 606, he discovered one that was safe in humans, but a deadly poison for the spirochete responsible for syphilis. The resulting medicine was called Salvarsan, a transformative medicine for which Ehrlich is best known and a contributing factor in his receipt, along with Élie Metchnikoff, of the 1908 Nobel Prize in Medicine and Physiology.
After Ehrlich’s death in 1915, the street in Frankfurt where his famous laboratory made this discovery was renamed in his honor; it was renamed again during the rise of the German National Socialist Party’s systematic attempt to erase its Jewish citizenry from national memory.
16. Commercially available laboratory mice are a relatively recent phenomenon, and most come from the grounds of the Jackson Laboratory in Bar Harbor, Maine, on Mount Desert Island. The modern lab mouse has roots in the various strains favored by late-nineteenth-and early-twentieth-century “mouse fanciers” as exotic pets, and are a genetic mix of four distinct and geographically disparate mouse subspecies: Mus musculus domesticus (from Western Europe), Mus musculus castaneus (from Southeast Asia), Mus musculus musculus (from eastern Europe), and Mus musculus molossinus (from Japan). According to Jackson Laboratories, many inbred mouse strains originated in the early-twentieth-century colonies of Miss Abbie Lathrop, a mouse fancier and breeder from the dairy land of Granby, Massachusetts.
17. These mice are also called “athymic” or “thymus-lacking.”
18. In January 2018, researchers affiliated with the Parker Institute for Cancer Immunotherapy announced the discovery of a molecule called BMP4, which, in mice, helps to promote thymus repair and even regeneration of the organ. The results, published in Science Immunology, were developed in the lab of Dr. Marcel van den Brink at Memorial Sloan Kettering Cancer Center, in collaboration with Jarrod Dudakov at the Fred Hutchinson Cancer Research Center. BMP4 will next be explored in humans, with the possibility of drug development for revitalization of the organ and the attendant quality of T cell response in humans. The thymus may be damaged by disease and is diminished as we age and is theorized to perhaps be related to the reason older persons are more susceptible to certain cancers. See Tobias Wertheimer et al., “Production of BMP4 by Endothelial Cells Is Crucial for Endogenous Thymic Regeneration,” Science Immunology, 2018, 3:aal2736.
19. Timing is everything in such experiments, and it’s important not to accidentally cast a scientist doing good science and conducting hard skeptical tests on scientific theories—as scientists are supposed to do—in the light of a villain. Stutman used nude mice, athymic mice. He was right that they lacked a thymus, right that the thymus was where T cells matured, and right, even in 1974, that those T cells were responsible for adaptive immune responses. But what Stutman didn’t realize—nobody did at the time—was that these mice still had other cells from the nonadaptive immune system, called “natural killer cells.” They are somewhat the grunts of first-line, basic immune defense in the body, nothing like the trained elite special forces of the T cell army, especially the “serial killer” CD8 killer T cells—but they are present, and can kill modest and obvious invaders. Meaning, he hadn’t obviated the possibility that immunosurveillance was in fact still intact in his experimental mice. Perhaps more important, the specific genetic strain of nude mouse that Stutman had used was explosively susceptible to developing tumors from the carcinogen he had used. His mice might have been overwhelmed by tumor development, to which no level of immune surveillance could have kept pace.
20. Osias Stutman, “Delayed Tumour Appearance and Absence of Regression in Nude Mice Infected with Murine Sarcoma Virus,” Nature, 1975, 253:142–144, doi:10.1038/253142a0.
21. It would later be discovered that nude mice aren’t quite as nude as you’d think; they do have small numbers of T cells and “natural killer” cells, whose role in immune surveillance is still unclear. Also, the nude mice strain Stutman had used would later be discovered to be especially susceptible to 3-methylcholanthrene, especially at the large doses Stutman had used, which would cause cancerous mutation in even the strongest mouse immune system.
22. It was possible to build a mouse in which they’d knocked out the gamma interferon receptor. Or they could make a mouse that lacked a signaling protein necessary for gamma interferon to function. They had already made that second mouse in Bob’s lab. Or, another way to get there, a knockout mouse. They could use a mouse that had no lymphocytes—no B cells or T cells, and therefore, no adaptive immunity. They had some of those mice available, too, what were called “RAG knockout mice,” in which the gene for lymphocyte production had been knocked out genetically.
23. Key to this experiment’s quality—the lack of “garbage in”—was ensuring that the carcinogen used was not one that all of the particular breed of mouse being used in the experiment had carcinogenic affinity for, as Stutman’s had, and ensuring that the amount of carcinogen delivered was a minimally efficacious dose for tumor development. Stutman had unwittingly overwhelmed his mice with a cancer that no immune system, intact or otherwise, could match.
24. “Another issue was, we were confronted with the argument, ‘Hey, I’m a tumor biologist, and I make oncogene-driven tumors, and I never see a role for the immune system in my oncogene-driven tumors,’” Schreiber says. “We only discovered recently that these oncogene-driven tumors—which are the experimental model of tumors—don’t develop any mutations, or at least few. So if they’re not particularly immunogenic, it’s only because they don’t have neoantigens.”
25. Schreiber: “You know, you can have deletion of your tumors, elimination. You can have modification of your tumor, so it might be held as sort of an idea, as a… dormancy that we call equilibrium. And it could be altered in such a way, just as you might alter a manuscript, that it would come out as a better tumor.”
26. That became a Nature paper, too.
27. “We began to look at the tumors that we had passaged in vivo and chart their progression versus regression growth characteristics and using a genomics approach.”
28. “One tumor had a very strong mutation in a highly expressed protein. The protein was present before we put it in the in vivo passage [i.e., before it was transplanted into the living animal], but then it was gone in the tumor cells that grew out [that is, the daughter cells from that transplanted tumor]. And it turns out, that was the neo-antigen that was seen by the immune system. That allowed the tumor to be rejected spontaneously. “And eventually this evolved into the whole idea of, ‘Oh, well, this is a pretty good idea, because it turns out that the T cells that get activated by the checkpoint antibodies like anti-PD-1 and anti-CTLA-4, those T cells are actually against these tumor-specific neo-antigens.’”
29. Gavin P. Dunn, Lloyd J. Old, and Robert D. Schreiber, “The Three Es of Cancer Immunoediting,” Annual Review of Immunology, 2004, 22:329–360.
30. Jim Allison had helped find those checkpoints, developed inhibitors against them, and was in the process of trying to get those drugs into the clinic, to see if they worked on humans as an immunotherapy against cancer.
31. Dunn et al., “The Three Es of Cancer Immunoediting.”
32. Daniel S. Chen, Ira Mellman, “Oncology Meets Immunology: The Cancer-immunity Cycle.” Immunity, volume 39, issue 1:July 25, 2013, 1–10.
33. MDX-101 was developed in transgenic mice at Medarex by a team led by Alan Korman.
34. The anti-CTLA-4 antibody (MDX-010) was a human immunoglobulin antibody derived from transgenic mice having human genes. This antibody had been shown to bind to CTLA-4 expressed on the surface of human T cells and to inhibit the binding of CTLA-4 to its ligand (B7 molecules, expressed on antigen-presenting cells).
35. “Before clinical use, MDX-010 anti-CTLA-4 Ab [antibody] underwent extensive evaluation in cynomologus [macaque] monkeys and did not cause any notable clinical or pathological toxicity at repeated i.v. doses from 3 mg/kg to 30 mg/kg in acute and chronic toxicology studies (unpublished data from Medarex).” Giao Q. Phan et al., “Cancer Regression and Autoimmunity Induced by Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma,” Proceedings of the National Academy of Sciences of the United States of America, 2003, 100:8372–8377, doi:10.1073/pnas.1533209100, http://www.pnas.org/content/100/14/8372.full.
36. Phan et al., “Cancer Regression and Autoimmunity.”
37. “All of these patients had undergone surgery to remove the primary tumors, almost half had tried chemotherapy, and almost 80% of these patients had already undergone some form of immunotherapy; that included IFN-α (patients 2, 5–8, 10, 12, and 13), low-dose IL-2 (patients 2, 5, and 13), high-dose IL-2 (patients 4, 7, and 8), whole-cell melanoma vaccines (patients 1, 2, and 6), NY-ESO-1 peptide vaccine (patients 4 and 5), or granulocyte-macrophage colony-stimulating factor (patient 9).” Ibid.
38. The most dramatic of these patient stories was a woman who had barely passed the physical requirements for participating in the study. She had tumors collapsing one of her lungs and even more filling her liver, and all previous measures to stop the disease had failed. After a small, single test dose of the anti-CTLA-4 antibody she had gone into rapid remission, and by the time she left the study completely she had no evidence of the disease; the tumors had all disappeared. This complete response would turn out to be durable as well; fifteen years later this patient is still cancer-free. Dr. Antoni Ribas was clinical lead for this groundbreaking clinical study and a recognized leader in making anti-CTLA-4 a success.
39. Phan et al., “Cancer Regression and Autoimmunity.”
40. Only fourteen had been able to complete both phases of the trial.
41. “We’d tested against a lot of tumors in mouse models, and eventually we realized that tumors that have a lot of mutations, and therefore a lot of neo-antigens, respond well,” Allison says. “Those that don’t, don’t.”
42. It originates on the part of the body (skin) most exposed to UV from sunlight and other outside carcinogens, resulting in tumors marked by a high number of mutations.
43. Those small mutational changes were often enough to allow melanoma to get “lucky” and escape whatever cancer drugs were being thrown at it. One drug would work and kill most of the cancer cells, but the remaining cells continued to mutate, and if one of those mutations happened to be resistant to the drug, that cell survived, and continued to divide. The new, drug-immune cancer would come roaring back, and the process would begin again with another, less effective therapy. The patients who would be enrolled in a clinical study for an experimental treatment had already tried all the available treatments. Their melanoma had beaten them all.
44. He’d seen the relief of the lucky fraction of metastatic melanoma patients who responded to chemotherapy, and then watched only a few months later as the cancer came roaring back, mutated and stronger than ever.
45. One reason is that he entered the field, incredibly, as a teenager, mentored by giants in the immunotherapy field. The other is that he works constantly, a habit he was raised with. He grew up with a father who was a Teamsters official and taught at New York City community colleges at night, and a mother who somehow survived a life spent as a New York City elementary teacher. (This hard work trait is common to good doctors everywhere, but somehow nearly universal among the immune oncologists I spoke to, many of whom end up married to lab partners or other immune oncologists, so they never have to talk about anything less important or interesting. Others, like Steve Rosenberg at the NCI, seem to live on burned coffee and treat the lab as home.)
The traits combined while Wolchok was still in high school and took a summer job in a Cornell immunology lab, working directly with patients and vaccines. It doesn’t get much more direct than that—except that it did the following year, when he went to college and met Lloyd Old. Old recognized the interest and potential in the wunderkind and in 1984 introduced him to Alan Houghton, the freshly tenured chair of immunology at the vaunted Memorial Sloan Kettering Cancer Center. Cancer immunology wasn’t exactly the obvious choice for a Staten Island kid paying student loans to become a doctor—there were easier ways to make good. But Wolchok is passionate and compassionate and intellectually driven. Like his friend Dan Chen on the West Coast, he could think of nothing more interesting or useful than combining an MD with a PhD and translating lab work to real people who needed it.
With Old and Houghton behind him, his path was set, if he wanted it, and once again, Jedd Wolchok, as he puts it, “raised his hand for that.” That summer he was helping out with a phase 1 clinical study using an antibody targeting melanoma, in the lab by night, with the patients by day, living in the intersection of science and medicine, with living proof, in the form of his “anecdotal” responders. The immune oncology worked and was real. It all clicked, and the course of his life was set when he was just nineteen years old. And while it’s difficult to imagine a cancer immunology origin story that tops those name checks, now here he was more than a decade later, partnered with Jim Allison on the clinical study that would change everything.
46. Immune oncology wasn’t the safest career path, especially if you had the education and the pedigreed training to work anywhere, including on therapies that were actually showing progress. That was why he knew Dan Chen—essentially, how could he not know another Gen-X MD-PhD oncologist specializing in melanoma and intellectually dedicated to beating it through immunology? People like that—Pardoll, Hodi, Butterfield, Hoos—were scarce compared to the chemotherapy-focused oncologists. That was the normal way—studying approaches to attack the tumor with drugs, rather than trying to figure out how to unleash the immune system to do the job. It wasn’t the intellectual position you would expect from an otherwise promising young kid from Staten Island with decades of education, training, and student loans under his belt.
47. For Wolchok, one of those glimmers came in what seemed to most a failure: the test of interleukin-2, or IL-2, a cytokine or immune hormone. IL-2 was heralded as the success of the age, the game changer—it was seen, at the time, as the potential breakthrough. But once it was cloned in sufficient quantity to begin large-scale, systematic testing on patients, it didn’t work as predictably as had been hoped. Instead of a breakthrough, IL-2 was declared a failure, as was the quest for a means to use the immune system against cancer with it. The experience set the public face of immunotherapy back decades.
Looking back at the data from those IL-2 trials, 3 to 5 percent of patients had positive responses to the immune hormone injections. But the patients who did respond were patients with melanoma and kidney cancer. And that group proved to be a small but reproducible number. That reproducible data showed researchers that IL-2 led to the growth and differentiation of T cells. The exact biological mechanism of how it did so wasn’t fully understood, and nobody yet knew that cancer took advantage of blocked immune response, such as CTLA-4 (which blocks general immune mustering of T-cells) and PD-L1 (which tumors express to put the brake on the T-cell at the moment it’s targeted the tumor for attack).
And so the public opinion of IL-2 failure as the breakthrough against cancer was seen rather differently by some scientific researchers. It stomped on the spirits of many cancer immunotherapy faithful, even as it increased their faith in the concept of cancer immunotherapy. There, in black and white, were trials that showed that a drug (a cytokine, in this case) could in some patients lead to durable and profound immune responses—and long-term regression of cancer. The numbers were low, but they were reproducible. It wasn’t a success, from a drug perspective, but for Wolchok and a handful of others, that was the first glimmer that proper modulation of the immune system could lead to durable control of tumor growth. It was proof of concept.
“People said, ‘Oh, [IL-2] is too toxic. It doesn’t work in many people’—and all of that is true,” Wolchok says. “But it did show us that under certain circumstances—circumstances which we didn’t completely understand at the time—the immune system could recognize cancer. And the immune system could control it. So, we had these glimmers. You start to put these different pieces together—you had the small reproducible successes of IL-2, you had the mouse models, you had the veterinary oncology—glimmers and glimpses. But [to the larger scientific community] this was considered extremely misty. And there were a lot of points to connect.”
What was missing was some hard science—basic research into the misty workings of the immune observations they’d been making. And more than anything else, what they needed at that point was the missing puzzle piece, or maybe a complex of pieces that connected all the glimpses and glimmers, and turned the anecdotes into science. Chemotherapists and the majority of oncologists thought that this hope without proof was a bit flaky and rather misguided. But for the immune oncology faithful, this was exactly what a complex biological pursuit would look like. Yes, immunotherapy didn’t work, but that didn’t mean it wouldn’t or couldn’t. It was like they were trying to start a car; they’d seen other cars running fine, they’d observed that the engine sputtered but wasn’t reliably turning over. Yes, definitely, they couldn’t figure out why it wasn’t running. But they still believed it was a car.
They believed that something real and specific was preventing the engine from turning over. They believed that the parts of the car they knew about—the ignition, the engine—all existed and were crucial to making the car go. They’d observed it running occasionally, seen other cars that ran, and were now finally working out all the mechanics of the system—the key that needed to fit, the gas pedal and lines, aspects of the engine, requirements of fuel and temperature and flammable gases. Given all their understanding, they still couldn’t make the car go. Sometimes, even when they could make the engine run, they still couldn’t make it go forward. To immunotherapy researchers, that meant that there had to be another necessary part yet to discover, a mechanism they’d failed to understand. And they believed that if they kept trying, sooner or later they’d discover that thing. It would be the breakthrough that explained the problem. It was hopeful and inspiring, and then, like most immunotherapy at the time, frustrating. “You could see it working in the mouse models. But the challenge was to take what you’d seen in a 20-gram lab mouse, inbred and eugenically identical to every other mouse you’re studying, and then try and translate that to a 70-kg outbred human,” he says. And from there, they could make the car go, and start to work on better and different cars.
48. “We believed that under certain circumstances, you can develop protection from cancer by the immune system,” Wolchok says.
49. At the time Wolchok was trying to develop cancer vaccines, and in an effort to overcome some regulatory hurdles, they started with clinical trials in dogs—not sad lab animals but people’s pets, some he knew personally. Just like people, most of the dogs were outbred genetically, which is to say, they were mutts. And just like people, these pets had developed melanoma by an unfortunate interaction between genes and environment. In the dogs, his vaccines worked—“We showed that we could in fact change the life expectancy of a dog with metastatic melanoma by vaccinating it,” he says. “The results were some happy dogs and dog owners and the first approved cancer vaccine (though it’s only for dogs).” But the larger point was that Wolchok had seen an immuno-oncology treatment work with his own eyes. The vaccines wouldn’t be the same, but the theory was identical: The immune system could be helped to recognize a mutated cell and kill cancer.
50. One of the most important conclusions was that the response rate they’d agreed to and set up is not in fact a terribly biologically relevant endpoint for testing the effectiveness of CTLA-4 blockade in cancer patients.
51. And he presents a very different vibe from the long-haired true believers that had dominated the field for a generation.
52. His triple-axel-and-a-somersault career had arced with mathematical precision, and now he’d stuck the landing. “Oh ya, it was good,” Hoos says succinctly. “The right things came together at the right time and after many years of failure and disbelief.” There was only one problem: That study he’d inherited wasn’t going to work.
53. As a standard it’s called “Response Evaluation Criteria in Solid Tumors,” or RECIST. RECIST is the set of rules governing clinical trials, and how to measure a patient’s tumor changes.
54. The problem with cancer isn’t the cancer you have, it’s the progression.
55. The unique language of cancer carries our collective history with the disease. Just as the name cancer conveys the image of a crab-like tumor, most probably a sarcoma, progressed to the point of bursting from the skin.
56. PFS describes a game of inches. It assumes the worst and counts small blessings. It also engenders a very specific way of thinking about the disease—in terms of the mechanisms of chemotherapy or radiation or small molecules that starve the tumor. These were the methods science was already familiar with. Over time, they became a habit and an intellectual blind spot.
57. The effects of radiation or chemotherapy upon a tumor target work in essentially the same way. The radiation sends tiny particles from a decaying isotope punching through the cells where it has been implanted like a miniature grenade. Chemotherapy essentially poisons them. The main force of the radiation or chemical attack is the tumor itself.
58. The primary investigators in charge of the Ipi studies were Dr. Steve Hodi (now at Dana-Farber Cancer Institute in Boston), Jedd Wolchok, Jeff Weber at USC, Khan Hanumui in Vienna, Steve O’Day at the Angeles Clinic in Santa Monica, together with Omid Hamid in Los Angeles and Dr. Ribas. They knew the numbers were bad.
59. “Mr. Homer” is not his real name; he is the patient referred to as case #2 in Yvonne M. Saenger and Jedd D. Wolchok, “The Heterogeneity of the Kinetics of Response to Ipilimumab in Metastatic Melanoma: Patient Cases,” Cancer Immunity, 2008, 8:1, PMCID: PMC2935787; PMID: 18198818 (published online January 17, 2008).
60. Sharon Belvin has now been totally cancer-free for more than twelve years. “We looked at her CAT scan,” Wolchok remembers. “The cancer was gone—all of it, gone—that does something to you.”
61. Saenger and Wolchok, “Heterogeneity of the Kinetics of Response.”
Six: Tempting Fate
1. The history of interferon is fascinating and popularly misunderstood (a very good treatment of the subject may be found in Stephen S. Hall’s A Commotion in the Blood). It’s also a case study in the difference between the public perception of what constitutes scientific breakthrough and true scientific advancement—a difference that can be summarized by the word medicine.
Like most science stories, the story of interferon starts with a mysterious observation, a phenomenon that had first been observed, or at least described and published in the medical literature, in 1937, when two British scientists noted that monkeys infected by a virus (in this case the Rift Valley fever virus) were somehow resistant to infection by the yellow fever virus. The concept of inoculation and vaccines was already familiar, but this was something new; the two viruses did not appear to be related, and in fact the Rift Valley virus was fairly weak, unlike yellow fever, which would have killed them.
The observation played out time and again in various cells and animals; exposure to one virus, usually a weak, nonfatal sort, somehow locked out infection by a second, even fatal virus. Because infection by the first virus interfered with the ability of the second virus to get a foothold in the host, the phenomenon was called “interference.”
The name given to the phenomenon says much about the time, and the way the mechanism was perceived to have worked, as if the first virus acted as a signal jammer for the second, the way a large radio tower broadcasting at fifty thousand watts crowds out smaller radio stations on the dial. In effect, the first virus seemed to create a sort of invisible force field repelling and protecting against infection by the second virus—perhaps in the form of some generated chemical shield, or perhaps caused when the first virus consumed all the resources that viruses need, making a second infection impossible, or perhaps—well, the literature and lunch tables of famous medical research centers across the world were littered with what-ifs. The mechanism of it wasn’t understood at all, but its mystery seemed to be wrapped up in the secrets of the immune system and the biology of molecules and cells. Until you understood them, it was a nifty trick, if only a trick, but one with obvious potential practical application, and thus reproduced, in the 1940s and 1950s, in dozens of labs and causing an entire generation of scientists to look at viruses and virology as the most interesting and important topic on the block.
In 1956, the center for that research was in a series of unassuming buildings at the National Institute for Medical Research, a place located on a rise called Mill Hill, north of London. The United Nations’ World Health Organization labs were also headquartered there, with an early-warning World Influenza Center overseen by none other than C. H. Andrewes, the legendary virus researcher who had discovered the virus that causes influenza in the 1930s.
In June 1956, Andrewes’s lab was joined by a thirty-one-year-old biologist fresh off the train and ferry from Switzerland named Jean Lindenmann. Lindenmann’s employment in Andrewes’s lab was related to polio; there had been successes with the first generation of polio vaccines, and Andrewes hoped to improve upon it, but he needed great supplies of the virus to work it out with. Lindenmann was to attempt to grow the viruses in rabbit kidneys. He failed, but ended up collaborating on another experiment that was far more successful.
While most of the real scientific work happens inside the laboratory, story after story demonstrates that the lunchroom, where scientists speak about their findings and passions and exchange ideas with members of other laboratories, is the true breeding ground of invention. Just so were the famously overcrowded lunch tables of the Mill Hill canteen. It was here, hunched over his hurried lunch, that Lindenmann happened to find himself talking about his fascinating interference phenomenon with a charming and accomplished virologist named Alick Isaacs. Lindenmann was surprised to find that Isaacs had become fascinated with the magic of this interference thing, too. Isaacs was remarkably enthusiastic about it—not only because he happened to be a manic depressive on an upswing, which he was. As it happens, the young scientist had already gone ahead and conducted several experiments on the thing.
Lindenmann had an experiment in mind, too, one he believed would help answer a critical question: Did a virus need to actually enter a cell in order to imbue it with the magic “interference”? He hoped the answer could be made clear—visible, in fact—using the powerful new tool the lab had at its disposal: the electron microscope. At the very least, the experiment would bring them a step closer to understanding whether the interference force field was something that occurred around the cell (a phenomenon on the surface or immediate surroundings), or whether the switch had to be turned on from inside the cell. Isaacs was game.
2. Chen is well trained as both an immunologist and an oncologist. Nothing could be more interesting to him than the interface between his two chosen fields. But he wasn’t ready to go all-in on joining the ranks of the confirmed true believers of the immuno-oncology ranks, either. Maybe it was because he was raised to be practical, to keep his feet on the ground while moving toward a career, even if he occasionally glances up at the stars.
3. Chen and family are a fascinating bunch, scientific and yet theatrical, though cancer immunologists tend to stray from the nerdy and narrow scientific stereotype. Dan Chen loves music, science, collecting Pappy Van Winkle and other whiskeys, and Halloween houses, and he and Deb have built a family of three smart, kind, and talented kids—it’s all a bit intimidating on a visit. On top of that, one has to remember that his day job is literally curing cancer. “I love what I do,” Chen explains. “I live for this [cancer immunotherapy research] and there’s no gap between my personal life and my work life.” It’s a sentiment I heard often among those dedicated to the field.
4. Chen was a Howard Hughes Medical Institute associate at Stanford; he completed his internal medicine residency and medical oncology fellowship there in 2003.
5. Chen had contacted Dr. Weber again to see about getting him into a different, newer vaccine trial, but his bout with the previous vaccine made him ineligible for such a study. If Brad was going to stand a chance he’d need something else—something available now.
6. Dr. Chen: “It would require the ability to quickly and economically sequence the entire genome of both the patient and that patient’s cancer, a computer powerful enough to run bioinformatics on all that data and determine the best antigen target that would get a strong response to the tumor without creating a response against the patient, and the ability to turn that into a custom vaccine. We can do all of that now.”
7. Dr. Jeffrey S. Weber, MD, melanoma and immunotherapy oncologist, is currently at NYU Langone.
8. Working so closely with a patient like Brad was one of the reasons Dan Chen was perfectly happy at Stanford. He had his lab and his oncology practice. He didn’t have a specific interest in leaving that for what they call “industry”—working for a company, rather than a university research facility. His interaction with patients nourished him, and the academic setting was what he’d aspired to. What he wanted most was what his patients wanted—answers. Hope. New solutions. And during the time he was thinking that, an offer came for him in 2006 to join the team at the local biotech.
His first impulse was to ignore the solicitation. There was virtue in the university research setting, and he worried that there might be something mercenary in leaving that for a for-profit company. Besides, he had worked hard and built a good career in academia. He had a sharp young team assembled in the lab, he was pleased with his research, and he was publishing well and often. He was climbing the ladder. The university setting offered built-in stability, the sort his academic parents worked hard to accomplish for themselves and had always imagined for Dan, too. So he wasn’t inclined to leave that and not at all inclined to leave his patients, some of whom he’d been seeing for years. But when the call came, he didn’t see the harm in at least hearing what they had to say, and maybe having a meeting.
9. From: Daniel Chen < Subject: Melanoma
Date: Thursday, February 18, 2010, 5:30 PM
Hi Brad,
I received your message, and I’m certainly disappointed, as I’m sure you are. However, I am happy to hear that the recurrence appears to be occurring in the same place it was seen last.
-Did you ever get radiation treatment at that site?
-Have you had your tumor analyzed for the V600E bRAF mutation?
-Have you contacted Don Morton regarding surgical resection?
-Would you consider IL-2 treatment at this point vs. clinical studies?
10. Leslie A. Pray, “Gleevec: The Breakthrough in Cancer Treatment,” Nature Education, 2008, 1:37.
11. The so-called Philadelphia chromosome, or BCR-ABL, a fusion of two swapped genes found to be present in 95 percent of patients with a specific type of white blood cell cancer, chronic myelogenous leukemia (CML). The work, begun in the 1960s, was the first time a connection between a genetic condition and a predilection for cancer was realized. The drug remains transformative for that subset of patients.
12. “I wouldn’t say Ira was covert about it, but he wasn’t exactly open, either,” Chen says. Cancer immunotherapists were a special little minority. The larger body of cancer biologists looked at that special little group as being… different. Bad different. “Passionate,” is how Dan puts it, “but maybe overly passionate.” Which is how everyone else says “crazy.” The feeling seemed to be that they were a group for whom belief had clouded their scientific objectivity; they believed, and so they did not see. Declaring your faith in the promise of cancer immunotherapy at a drug company meeting was a surefire way to have your ideas discounted. “They thought it’s all bogus,” Dan says. “I think a lot of cancer biologists recognized the promise of the field. But a lot of them, I think, felt that the biology just wasn’t there, they just didn’t believe in it. It wasn’t the future. Especially since they’d discovered the oncogene for melanoma—that was the future, targeted therapy.”
The room was polarized between the cancer biologists and the cancer immunologists. In the middle was Scheller. The cancer biologists were excited about the identification of the oncogene that drives the mutations that turn a cell into melanoma. In the room, if it was a vote, it’s 50 to 80 percent certain that they’d want to develop a drug to target the transcription of the oncogene into melanoma.
13. Steinman died of cancer in September 2011, only a day before the committee quietly notified the winners.
14. Ira Mellman remembers they’d argue about it, but they’d never convince anyone.
“The challenge of immunotherapy is that it was a promise for a hundred years, OK? With breakthroughs always twenty years away,” Mellman says. “So the idea has been around probably for the better part of the century now, if not longer, that you can activate an individual’s immune system to combat cancer. But when that first hit—it hit about the same time as surgery did, and when radiation therapy did, so it was sort of pushed off in the corner, in part because so little was known about the immune system at that time, and in part because the work sucked, from a scientific perspective. And that motif remained for decades!
“The cancer biologists had the oncogene to point at. The cancer immunologists had some exciting new papers coming from cancer immunotherapy research, and some startling new data. The data was empirical, but what it meant was still open to interpretation and bias,” Mellman says. “You don’t argue the facts, but you argue the interpretation.” But for every study which suggested one truth about getting the immune system to recognize cancer, there was always another, seemingly just as credible, which suggested the opposite. The cell biologists pointed to the one, while the immunologists pointed to the other. There was no lack of data, numbers, studies, or the usual mouse models; they’d all seen them. And there were problems with mouse models. “They’re rarely predictive of humans” to begin with, Mellman explains. “The mouse models were always crummy.” Maybe one out of five worked. But the one that worked, worked really well. At the end of the day, the cancer immunotherapy cynics had the trump card, which Mellman paraphrases as “You don’t even know how any of this works.” And the worst part was, they were right. He adds, “The underlying mechanisms, the biology—if you don’t understand that, how can you tell us you really understand these new findings?” And the truth was, they couldn’t. Nobody understood the complex biology. And it was nearly impossible to make a solid scientific argument without the science to back it.
15. To figure out which T cell genes didn’t have anything to do with the self-destruct signal; the genes led to the receptor.
16. Y. Ishida et al., “Induced Expression of PD-1, a Novel Member of the Immunoglobulin Gene Superfamily, upon Programmed Cell Death,” EMBO Journal, 1992, 11:3887–3895, PMCID: PMC556898.
17. He is now codirector of the cancer immunology program at Yale Cancer Center in New Haven, Connecticut.
18. B7-H1, a third member of the B7 family, costimulates T-cell proliferation and interleukin-10 secretion. See H. Dong et al., “B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion,” Nature Medicine, 1999.
19. Lieping Chen had cloned the human PD-L1 gene and, he says, attempted to convince a company to produce a commercial antibody against it in 2001, without success.
20. The testing was done at NIH, initiated by Dr. Suzanne Topalian.
21. Dan Chen had to look no further than his own childhood dining room table. He could still see his father there, a physicist passionate about his work on equations to realize the dream of fusion.
“And it’s the same deal, right? A passionate group of scientists believe in fusion as the future of energy, and it was always twenty years away,” he says. “And now here we are, forty years later, and there’s still this passionate group, and it’s still twenty years away. And I think the worry was, you know, we’ve got the small steps. We knew the biology was there. But was it always going to be twenty years away when we had something that was really useful for patients? And so none of us could really say when the actual breakthrough that would make this useful for the majority of patients was going to happen.”
22. One of the arguments Dan made for immunotherapy was its value proposition, which he summarized through a story about a night he and Deb were having dinner at a friend’s house. Dan hung out in her kitchen drinking wine while his hostess chopped salad. As Dan recalls, he started telling his hostess about his work and the progress they were making against cancer. He was wrapped up in it, and excited. The trials had come back and shown the drug would help cancer patients live longer.
“Oh, that’s great!” she said. “How much longer?”
Dan remembers telling her. Sometimes it was a few months.
“That’s it?” she said. “I thought you were curing cancer!”
He heard himself explaining that, well, cancer was really hard, and these numbers are averages, and—but he was justifying what he himself was frustrated about. Yes, he was in drug development now, that was exciting. Yes, they were making progress, the same incremental progress, the weeks and months that add up to years. That had been the cancer therapy story for at least a generation, maybe two. He was chipping away. But he wasn’t breaking through. None of them were.
When the first cancer research labs had been set up in the early part of the last century, the cure was the goal. They believed it was possible. And why shouldn’t it be? Other diseases had been cured through directed study and good science and a great deal of money. New technology was slowly cutting a swath through the forest of plague and pestilence that had hectored mankind for eons. The best minds were in the field. And one hundred years on, they’d made definite improvements for cancer patients. But they hadn’t found a cure.
23. At the time it was known the molecule they’d found was a protein expressed on tumor cells, but its connection to a receptor on the T cell, or the notion that interaction with that receptor would down-regulate T cell response, was not even guessed at. Instead the protein was seen as a potential target on tumors, a sort of molecular bull’s-eye that you could target with a corresponding antibody. A more typical drug development approach to cancer at that point was to then attach that antibody to some sort of poison you wanted delivered to the cancer cell. That was the process of drug development the team was headed toward when the immunologists in the room steered them off course.
24. “Everyone was willing to accept that PD-L1 might work in melanoma and kidney cancer,” Chen explained. These highly mutated cancers (especially melanoma) had also seen promising results with anti-CTLA-4. “But, even internally, the skeptics would say, ‘I’ll believe it when it works in lung cancer.’”
25. Another type of T cell, called a T regulatory cell, or T reg. The role of these cells is still being explored, but they are increasingly understood to be critical players in the checks and balances of immune response; they are, in a sense, cells always looking to call a truce to immune battle. It has not yet been definitely determined which is the more important influence, stimulation of T cell response or down-regulation of the T regs; in all likelihood both may end up being important.
26. “I was close with Brad,” Chen says. “That friendship made the highs more extreme and personal. And it made the lows personal, too.”
Seven: The Chimera
1. Dr. Michel Sadelain, comments to the author.
2. Based on the work of Tak Mak and others.
3. “Zelig made the receptor, I put it into T cells,” Hwu says. They started using patient’s T cells against melanoma, and then retargeting those TILs for ovarian, colon, and breast cancers. The ovarian cancer retargeting worked best of the three—the reengineered T cell recognized the antigens of the IGROV ovarian cancer cell line. “The first time I got that to work I was so elated,” Hwu remembers. But successful retargeting was only one part of engineering a successful cancer-killing machine. Such a cell also needed to be able to stay alive in the body, replicate into a clone army, and successfully and selectively kill the targeted cancer. In these regards, the cells reengineered at the NCI did not work.
4. This CAR-T was a far cry from the model T-body of 1985, a sleek, complex killing machine. “The first-generation CAR could, when put into a T cell, recognize the target molecule and kill the cell,” Sadelain explains. But they also must proliferate—they must grow and clonally expand. They must also remain functional T cells and retain that function over time. That required further modifications. Sadelain’s innovation was to introduce a costimulatory signal and produce what he calls a “second-generation CAR” that recognizes a target, expands clonally, and retains its other T cell functionality. Such a cell is “a living drug,” with a life span as long as that of the patient it lives in. This work was based out of his lab at Memorial Sloan Kettering Cancer Center, where Sadelain is the founding director of the Center for Cell Engineering and head of the Gene Transfer and Gene Expression Laboratory.
In 2013 Sadelain formed a company called Juno Therapeutics to exploit the new CAR-T technology, together with his wife and coinvestigator, Isabelle Rivière, and partners Michael Jensen, Stan Riddell, Renier Brentjens, and Fred Hutchinson Cancer Research Center immunologist (and Jim Allison’s Deadhead pal) and true-believer immunologist Phil Greenberg. The race was on to turn the potential killing machine into a more effective weapon against cancer.
5. Dr. June had based his CAR design on a sample he had requested from Dr. Dario Campana, then of St. Jude Children’s Research Hospital, after hearing a presentation by Dr. Campana at a 2003 conference.
6. The CD19 protein target selected by Sadelain was an essential aspect of the success of CAR-T and, in essence, he says, launched the field. “CD19 was known, but it was not a star when I selected it,” he explains. The criteria for a good molecular target for a CAR to recognize was that it be unique to cancer; if the antigen was found on cancer cells but also expressed in normal body cells, the CAR-T would attack both the cancer and the host. CD19 was a good choice, because it was an antigen that was heavily on the surface of certain cancers such as lymphoma. It also is expressed by some B cells, but that was collateral damage that was survivable; physicians have long experience keeping patients alive without B cells. “Facing terminal cancer, losing your B cells isn’t so bad,” he explains.
In a 2003 paper in Nature Medicine, his group showed that you could collect T cells and introduce a retroviral vector that coded for a second-generation CAR that recognized and targeted CD19 in animal models (immunodeficient mice given human genes and human CAR-T cells). That proof of concept in a preclinical model would then need to be approved for testing in a clinical setting—and the decision to allow genetically engineering a killing machine that targeted human proteins to be tested in a human subject would need to be carefully considered by the Recombinant DNA Advisory Committee (RAC) as well as the FDA.
7. And his CAR was gassed up by also expressing a costimulatory protein (called 4-1BB) that was similar to CD28. The result, they hoped, was a CAR with a steering wheel pointing it where they wanted it to go, and enough fuel to keep the T cell going long enough to get there and finish the job.
8. In 1991, Arthur Weiss of the University of California, San Francisco, developed a chimeric antigen receptor (CAR) called CD4-zeta as a means of studying the activation of T cells. See Jeff Akst, “Commander of an Immune Flotilla,” Scientist, April 2014.
9. GVAX was based on work that combined the cutting edge of gene therapy with that of immunotherapy. It was focused toward what was seen as the most promising direction for cancer immunotherapy at the time: the development of a cancer vaccine.
The treatment took a piece of a patient’s tumor, altered the tumor cells’ genes so that they would express a cytokine (called granulocyte-macrophage colony-stimulating factor, or GM-CSF, which had recently been shown to be involved in getting dendritic cells to present tumor antigen to T cells, work done by Ralph Steinman), and then reinject the modified tumor as a sort of double-duty vaccine, altering the immune system to the tumor while producing cytokines that stimulated the response. That was the theory anyway, but like all cancer vaccine trials during the 1990s and early 2000s, it failed, and the work was essentially shelved in 2008. The reason for such failure isn’t certain, of course, but much more is now known about the biology of the immune system, cancer, and the immunosuppressive tumor microenvironment, including the expression of PD-L1.
This was a fascinating chapter in the immunotherapy story, involving MD-PhDs now recognizable as a veritable who’s who of cancer immunology, including Glenn Dranoff, Richard Mulligan, Drew Pardoll, Elizabeth Jaffee, and others. Each of these researchers and scientists deserves a chapter in this book, and nearly all of them are currently doing important work that will surely write the next one. (Elizabeth Jaffee, for example, is working with GVAX in combination with an anti-PD-1 checkpoint inhibitor, nivolumab, in pancreatic cancer. Another combination approach is being evaluated by Aduro Biotech partnered with Novartis, where Dranoff heads oncology drug development, and Pardoll is codirector of cancer immunology and Hematopoiesis Program Professor of Oncology at Johns Hopkins in Baltimore.)
That original 1993 academic paper that laid out the scientific foundation and therapeutic claims for GVAX can be found here: Glenn Dranoff et al., “Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity,” Proceedings of the National Academy of Sciences of the United States of America, 1993, 90:3539–3543.
Incidentally, Dan Chen had presented this paper for his journal club while still a medical school student, and it had provided a spark of interest that helped shape his career. Years later he would marvel that those researchers were now his peers in the small world of immunotherapy. Or, at least, a world that was small until the breakthrough.
Several of these fascinating and critical players in the immuno-oncology world were also interviewed by Neil Canavan, a writer and researcher with the biotech venture capital firm the Trout Group, for his book A Cure Within: Scientists Unleashing the Immune System to Kill Cancer (see “Further Reading,” following the appendixes).
10. June still remains dedicated to research for ovarian cancer specifically, as well as for the blood cancers currently targeted by CAR-T therapy.
11. Children who undergo chemotherapy and radiation for the treatment of blood cancers are often cured, but they suffer as adults do not—one of the reasons that children with leukemia are now eager to skip those therapies and go directly to CAR-T. Learn more at EmilyWhiteheadFoundation.org.
12. The Whiteheads had originally sought a second opinion at the Children’s Hospital of Philadelphia and wanted to pursue the CAR-T therapy, but the FDA had not yet approved the therapy for pediatric patients. Pediatric therapies get a more rigorous and thus slower vetting than adult therapies, which physicians like June find frustrating, especially when patients’ lives depend upon them.
13. Because viruses are agents of infection that cannot reproduce on their own, scientists are not in total agreement as to whether viruses merit a branch on the tree of “life,” as we define it; they are mobile molecular assemblages that to some more closely resemble tiny organic machines than living creatures.
14. The scene, as reported by several outlets at the time, was remarkable and, like all children’s cancer wards, heartbreaking. Emily lay on the hospital bed in a sparkly purple dress, bald and browless from the failed chemotherapy, a pressure cuff around her thin arm. The feeding tube snaking up around her ear and into her nose was held fast by pediatric tape, purple to match the dress.
15. James N. Kochenderfer et al., “Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated with Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor,” Journal of Clinical Oncology, 2015, 33:540–549.
16. Dr. Grupp is both Children’s Hospital oncologist and the principal investigator of the CART-19 trial in children. See Jochen Buechner et al., “Global Registration Trial of Efficacy and Safety of CTL019 in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Update to the Interim Analysis,” Clinical Lymphoma, Myeloma & Leukemia, 2017, 17(Suppl. 2):S263–S264.
17. We now have strong evidence suggesting that it is not the engineered T cells themselves that release the IL-6, but rather it is the macrophages (blob-like elements of the innate immune system) that surround the attack upon cancer and do the cytokine releasing. In June 2018 Dr. Sadelain’s team at Memorial Sloan Kettering Institute released a letter in the journal Nature Medicine detailing this finding, as discovered via their CRS mouse models. One hope from this finding is that they will be able to identify the specific chain of molecular events in the cytokine cascade and block those that cause the dangerous symptoms, without interfering with those cytokines necessary for the coordinated immune attack. In doing so, CAR-T therapy may become less toxic and can be performed outside of a hospital setting.
Another hope is to take some of the variability out of CAR-T therapy, which, as a personalized medicine, varies in intensity from person to person. CAR-T is a unique drug in that it replicates itself in the body (unlike most drugs that are depleted by use), but not all T cells are equal. Those from a healthy immune-competent patient will replicate more prolifically than those of ill or older patients, or of those whose immune systems have been compromised by disease or chemotherapy. This makes dosing difficult for the clinician. Too few CAR-T cells results in an inadequate cancer-killing response; too many results in toxicity and CRS. See Theodoros Giavridis et al., “CAR T Cell–Induced Cytokine Release Syndrome Is Mediated by Macrophages and Abated by IL-1 Blockade,” Nature Medicine, 2018, 24:731–738, doi:10.1038/s41591-018-0041-7.
18. As well as another cytokine-dampening drug, etanercept.
19. Tocilizumab is now co-indicated for CRS and is used on CAR-T patients.
20. James N. Kochenderfer et al., “Eradication of B-Lineage Cells and Regression of Lymphoma in a Patient Treated with Autologous T Cells Genetically Engineered to Recognize CD19,” Blood, 2010, 116:4099–4102, doi:10.1182/blood-2010-04-281931.
21. In the New York Times, writer Andrew Pollack relayed a telling story about Steve Rosenberg as told by Arie Belldegrun. Prior to heading Kite Pharma, the National Cancer Institute’s corporate partner in commercializing CAR-T, Belldegrun had been one of hundreds of former research fellows whom Dr. Rosenberg trained and mentored over his career. At the time, Belldegrun had been trying to recruit Rosenberg to join his company, an offer that would have certainly made Dr. Rosenberg a very rich man (in 2018 Belldegrun and his partner sold Kite for more than $11 billion).
“He sits quietly, quietly, quietly,” Belldegrun told Pollack, “and then he asks, ‘Arie, why don’t you ask me what I want to do?’
“He said: ‘Every day that I go to work, I’m as excited as a kid coming to a new place for the first time. If you ask me what I want to do, I want to die on this desk one day.’” (See Andrew Pollack, “Setting the Body’s ‘Serial Killiers’ Loose on Cancer,” New York Times, August 2, 2016.)
22. The generic name for this CAR-T is axicabtagene ciloleucel.
Eight: After the Gold Rush
1. Another early therapy from this proof-of-concept era, approved a year before Ipi, was a dendritic cell therapy developed by a company called Dendreon. The drug, sipuleucel-T, failed to become commercially viable.
2. A partial list of those those PD-1 blocking agents starts with pembrolizumab (trade name Keytruda, developed by Merck pharmaceuticals and approved in 2014) and nivolumab (trade name Opdivo, developed by Bristol-Myers Squibb and approved in 2015). The drugs targeting the tumor side of the handshake (anti-PD-L1) rolled out soon after. One was atezolizumab (trade name Tecentriq), developed by Genentech and Roche pharmaceuticals, which received its first FDA approvals in 2017) and durvalumab (trade name Imfinzi), manufactured by AstroZenica and MedImmune and approved in 2018.
3. A May 2018 letter to the New England Journal of Medicine reported on a subset of patients whose tumors had been shown to grow, rather than shrink, during a phase 2 clinical trial of the PD-1 checkpoint inhibitor nivolumab (Opdivo). These patients had an aggressive and relatively rare form of cancer that affects the T cells, called adult T cell lymphoma-leukemia (ATLL). Lee Ratner et al., “Rapid Progression of Adult T-Cell Leukemia-Lymphoma After PD-1 Inhibitor Therapy,” letter to the editor, New England Journal of Medicine, 2018, 378:1947-1948.
4. In the battle metaphor, blocking that checkpoint tells the army to grow and arm and prepare to attack. PD-1 / PD-L1 is a checkpoint that happens later, up close and personal, after the T cell army is already mobilized and ready.
5. Immunologists now categorize the interaction between an individual’s immune system and their specific tumor into three broad classes: “hot, cold, or lukewarm.” The categories are useful in describing how different tumor types, and different immune systems, present a range of dynamics which need to be addressed by different drugs or drug combinations.
“Hot” tumors are the ones most recognized by the T cells. Under the microscope you can see them massed at the tumor, and infiltrating inside the tumor (“tumor-infiltrating leukocytes”). They’re there, and yet the T cells fail to complete the job and attack and kill the tumor. Also, these hot tumors may have various ways of “exhausting” T cells so that they cannot be “reactivated.” (Remember that the immune system has a series of safeties and circuit breaker–like or timer-like elements to prevent every immune response from snowballing into a full autoimmune nightmare; even effective vaccines require a “booster shot” to reactivate T cell response.) As a result, they are present but too spent to attack. Many of these tumors tend to arise in parts of the body that are most exposed to stuff that causes cancer, like sunlight, smoke, or other carcinogens. They include skin cancers (melanoma), lung cancers (small-cell and non-small-cell carcinoma), and cancers arising in organs that deal with concentrated levels of the stuff that goes into our bodies, such as bladder, kidney, and colorectal. For DNA in the process of replicating itself, these carcinogens are like a constant bombardment. It would be like trying to write out a recipe while being pelted with golf balls; the odds are pretty good that you’ll make plenty of mistakes. In cells, these mistakes are mutations, and as you’d expect, the cancers that arise in these carcinogen-exposed organs are characterized by the highest number of “mistakes” in their DNA, and have some of the highest levels of mutations. Mutations (for these or other genetic reasons) make them highly visible to the immune system, which make them “hot.” The fact that they’re seen but not killed by the immune system means that something else is also happening, a trick that lets them survive despite being mutational peacocks. In some cases, tumor expression of PD-L1 is one of those tricks, and as such, these tumors are the most likely to be expressing PD-L1, the secret handshake telling the immune system to pay no attention, despite all the antigens. As such they’re also the tumor types most responsive to checkpoint inhibitors (anti-PD-1 or anti-PD-L1). Right now, these are the “lucky” tumor types, most likely to respond to the available immunotherapeutic drugs—and when they do respond, the responses can be profound. It’s these tumors types that have oncologists willing to use the word cure.
An entirely different problem exists if the tumor is “cold.” The immune system almost entirely fails to respond to these tumors. Under the microscope, you may believe that we have no immune system at all, which is why cold tumors are sometimes described as “immune deserts.” These tumors are, for various reasons, less or not at all visible to T cells. Unlike their hot cousins, many—but not all—cold tumors are not highly mutated, and are not highly antigenic, meaning they don’t present themselves as obvious to the immune system by presenting antigens that are clearly foreign. In this case, immune therapies that “warm” the tumor up and make it more visible (more antigenic) might be employed (such as targeting the tumor with a virus to mark it with more obviously foreign antigens). Cold tumors may also employ other tricks that prevent T cells from effectively recognizing them. Those may be aspects of the tumor microenvironment—the little world created by the tumor itself—where molecules (in various ways) disable or suppress the full immune response (which is also referred to as a “suppressive TME”). The majority of a tumor mass is not cancer, but components of the tumor microenvironment. And it’s a tough neighborhood for a T cell to infiltrate.
Nature is conservative in that it doesn’t tend to evolve complexity when simplicity is successful. To generalize, that’s the reason most cold tumors don’t respond to checkpoint inhibitors: They’re the least likely sort of tumors to need a secret handshake like PD-L1 in order to survive and succeed. Their low mutation profile already makes them less visible to the immune system. With no checkpoint being taken advantage of by the tumor, inhibiting it will not change the situation.
And so as you’d expect, cold tumors respond poorly to the existing checkpoint inhibitors alone, and several types don’t respond at all. To imagine why, it’s useful to think of these tumors in terms of evolution. If a mutated cell is obvious to the immune system, the immune system sees it and kills it. The more mutated, the more obvious it is, and the less likely it is to survive and grow and become what we’d call cancer—unless it has also evolved a trick to compensate for its visibility. PD-L1 is one such trick. Cold tumors simply don’t need such a trick.
A third tumor type is generally, if not helpfully, called “lukewarm.” These tumors are seen by the immune system, the T cell army masses. But then, for some reason, the attack never happens. The T cells don’t infiltrate, they don’t destroy the tumor. Immunologists sometimes compare this to an army that has heard the battle call, massed at the castle, but cannot cross the moat. This category covers a wide variety of cancers and mutation types, and it would be incorrect to typify these cancers by any single factor. Unlike their description, it’s not simply that these tumors successfully evade immune attack due to some averaging or combination of hot and cold attributes—though aspects of both may be true. It’s most accurate to think of these tumors as having a unique profile of immune defense that allows them to survive and thrive without being totally invisible to the immune system. These tumors include some—but not all—glandular tumors. What matters is less often where these cancers arise than what typifies them.
In some cases, what makes them “lukewarm” is that despite being obvious, they exist in places that are difficult for immune cells to infiltrate. They may be typified by tumors with a tough outer layer that repels infiltrators. They may have evolved an almost fantastical outer line of defense. But generally, they are typified by a moderate expression of PD-L1, a moderate mutational load, a moderate antigen presentation, and often an immune-suppressive microenvironment that turns down immune response in the T cells at the gates. And there are some single therapies being tested to uniquely address these tumor types, but it’s fair to say that various elements of hot and cold tumor approaches—including checkpoint inhibitors, therapies to warm the tumor by making it more immunogenic, and approaches to counteract suppressive elements in the tumor microenvironment—may all be considered in changing the situation to one where they are recognized, targeted, infiltrated, and destroyed by the immune system. Here too, various stages of the cancer immunity cycle are being targeted to get those T cells across the moat (to become tumor-infiltrating leukocytes), activated, and recharged.
Nine: It’s Time
1. The footage is also now incorporated in the official music video of that Imagine Dragons song. See Jesse Robinson, “Imagine Dragons—for Tyler Robinson,” YouTube, October 27, 2011, https://www.youtube.com/watch?v=mqwx2fAVUMO.
2. The Tyler Robinson Foundation. Learn more at www.TRF.org.
3. Kim White wasn’t in the band, but she had been a member of their extended Salt Lake City crew, a fellow Mormon who had first met the lead singer when they were both teenagers. Jeff Schwartz knew her as the tall, pretty, young blond girl—“very pretty, very blonde”—who sometimes came to the show with her husband. Jeff saw her again at her benefit.
4. Kim has written about her cancer journey, which appeared originally on the Small Seed and is available on the Deseret News website at https://www.deseretnews.com/article/865667682/Utah-mother-I-am-now-and-will-forever-be-grateful-I-was-diagnosed-with-cancer.html.
5. The page has been live since July 2014 and has raised $16,075 toward a new $50,000 goal.
6. Kim White: “My husband had reached out to Mac [Mac Reynolds, singer Dan Reynolds’s brother and Imagine Dragons’ manager] and he was like, ‘of course.’ Originally it was going to be the whole band, but it was so crazy with everyone’s schedules, they were out of the country in the middle of a tour, so it was just Dan [Reynolds] who flew into Utah and did the benefit and they raised like $40,000 and he flew back the next morning.” The original plan also involved making wristbands as well, rubber ones people could buy and wear in support, and they needed a name to brand it with. They settled on “KimCanKickIt,” referring to the cancer, of course, as well as her love of soccer.
If you want to follow more of Kim White’s story she invites you to follow her at KimCanKickIt on Instagram.
7. She referred to her physician Dr. Boasberg as an “angel of a doctor.”
8. Manufactured by Merck as Keytruda, most commonly used to treat melanoma. Following the 2013 announcement of results from the study at the Angeles Clinic and elsewhere Merck applied for breakthrough designation for the drug so it could be both made immediately available and fast-tracked to approval, and it received that designation in September 2014. In the summer of 2016 a clinical trial testing the checkpoint inhibitor for use against small-cell lung cancer was stopped; the drug was proving so effective that the company and the FDA wanted to provide it to everyone in the study, rather than deprive the control group (patients receiving a placebo or other treatment) of the opportunity. It gained formal FDA approval for this cancer in March 2017.
Also in 2017 the drug was FDA approved for use against tumors that showed a specific mutation or genetic marker (microsatellite instability), making it the first drug to ever be approved for such an indication, and the first cancer drug to be approved for a genetic marker on a tumor rather than the organ in the body in which the mutated cell originated. This approval is hoped to be the first of many as tumor biomarkers are better classified and cancer cells genetically typed. If a tumor with a certain biomarker is known to respond to the drug, that is a far more efficient means of determining who would see benefit from it. This efficiency translates to patients trying to make crucial decisions about which therapy to choose, as well as to the drug companies responsible for conducting lengthy and expensive clinical trials for every type of cancer.
9. Clinical trials for drugs are specific to that drug being used as a therapy against specific cancers; while such drugs, once approved, can be used “off label” for unproven indications, it requires new clinical trials to access the safety and effectiveness of that therapy as opposed to others—an important distinction when patients often may not have time or health enough to try again.
10. Those original clinical trials were for melanoma; pembrolizumab was at that time called lambrolizumab. See Omid Hamid et al., “Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma,” New England Journal of Medicine, 2013, 369:134–144.
11. Kim’s experience with her rare form of cancer has made her an inspiration and example for others with adrenal cortical carcinoma. “As far as I know there are only four other people with it on that drug right now,” Kim told me. “Most people with it don’t respond.” But she did, and she immediately shared that on a group on Facebook for people with the disease, so they could try it, too. The anti-PD-1 drug did allow her immune system to successfully fight nearly all the lesions in her lungs, but it wasn’t the end of her journey with cancer. Eventually her Salt Lake City oncologist told her he could get Keytruda for her there, so she didn’t need to fly to LA every three weeks, which was inconvenient and expensive. “So that was great,” she says. Even the parking was better. “We’d fly to LA and we’d rent a car and have to park it for like an hour [for the treatment], and the first time I realized, you have to pay for parking and it’s like fifteen dollars and I was like, ‘What the heck is that? I’m definitely not in Utah anymore!’” The first months after she started recovery were the first she got to spend time with her daughter as something other than a terminally ill person. “That was really important,” she says. “She was only eighteen months old when this started, I’d never been anything else. So we spent those months backpacking, camping, really spending time.”
But despite continued treatment, “for whatever reason, the Keytruda doesn’t like my liver,” she says. “It doesn’t want to kill the cancer there.” And months later, she discovered that the remaining lesion had continued to grow. That required another surgery (“It was massive and they almost lost me, I almost died”), and the removal of 70 percent of her liver and a quarter of one of her lungs. “I spent a year recovering from that,” she says.
And she still is. Kim isn’t cured, but she’s alive, enjoying life despite the daily injections to thin her blood, the regular chemo she still receives, and a near-constant litany of tests and upkeep against the disease. “I definitely know it’s been a blessing,” she now says of the disease. “I’m a different person.” She appreciates each day, and her faith in a higher power is only strengthened as she continues to battle. “It saved my life and I’m grateful for that,” Kim says. “I never could have done it if the immunotherapy hadn’t made it possible.”
Appendix A: Types of Immunotherapies Now and Upcoming
1. Summarizing the current state of immunologic science creates an impenetrable list of what’s out of date before the ink is dry, and that list is long and growing. It grows each month from research around the world and new clinical data from the thousands of trials currently under way. Speculating on the therapies on the horizon is interesting, but not the goal of this book.
2. Among these are the new bispecifc T cell engagers, or BITE, developed by Amgen. BITE targeted CD19+(positive) B cell malignancies and were approved by the FDA in 2015 under the generic name belimumab; its trade name is Benlysta.
3. Including CD19, CD20, CD33, CD123, HER2, epithelial cell adhesion molecule (EpCAM), BCMA, CEA, and others.
4. Data from the phase 3 clinical trial CheckMate 227, presented at the AACR Annual Meeting in April 2018, showed that among patients with newly diagnosed advanced non-small-cell lung cancer with high-tumor mutational burden, those who received a combination of nivolumab (Opdivo) with ipilimumab (Yervoy) showed significantly improved progression-free survival (PFS) compared with patients who received the previous standard of care chemotherapy.
An American Association for Cancer Research press release cited Memorial Sloan Kettering Cancer Center associate attending physician Dr. Matthew Hellman in reporting that patients who got the combination immunotherapy were 42 percent less likely to show progression of their disease compared with patients who received chemotherapy, a near tripling of progression-free survival at one year (43 percent versus 13 percent, with a minimum follow-up of 11.5 months). The reported objective response rate for patients receiving the combination of checkpoint inhibitors was 45.3 percent, compared with 26.9 percent in those who received the standard of care chemotherapy.
5. Nikolaos Zacharakis et al., “Immune Recognition of Somatic Mutations Leading to Complete Durable Regression in Metastatic Breast Cancer,” Nature Medicine, 2018, 24:724–730.
6. There are several approaches to making an engineered T cell that both is compatible with the patient’s self tissues (and will not attack them as foreign), and also will not be itself attacked as non-self by the patient’s own immune system. Some use T cells taken from the cancer patient and bespoke-engineered against their specific cancer; others use a range of donated T cells to create a menu of off-the-shelf therapies compatible with different immune types (MHCs). A promising third route by Dr. Sadelain and others seeks to start from scratch by creating a “universal donor” T cell that can then be retrofitted to recognize whatever tumor antigens you choose. Advances in inserting genes into T cells, greatly enhanced by the advent of CRISPR technology, may allow for the construction of third-generation CAR-T cells, made in a culture from stem cells and capable of recognizing multiple targets, minimizing the toxicity of excessive cytokine release, perhaps even CAR-T cells engineered (or, more precisely, genetically edited) so that they are not susceptible to any of cancer’s tricks or down-regulation or exhaustion by factors in the tumor microenvironment.
7. Work in this field is being led by the lab of Dr. Lisa Butterfield at the University of Pittsburgh Department of Medicine and Bernie Fox at the University of Portland.
8. As an example, the target OX-40 was one of the most talked about when I started working on this book; now it’s not looking very promising. Another indoleamine 2,3-dioxygenase (IDO) breaks down a fuel (tryptophan) T cells need to proliferate and react. Preliminary combination study data has been confounding.